Yuan Gao

Hang Zhang

Frédéric Lirussi

Carmen Garrido

Xiang-Yang Ye

Tian Xie

Dual inhibitors of Histone Deacetylases and Other Cancer-Related Targets: A Pharmacological Perspective

Keywords: histone deacetylases (HDACs), dual inhibitor, anticancer drugs, kinases, epigenetics, enzymes, receptors, synergistic effects

Epigenetic enzymes histone deacetylases (HDACs) are clinically validated anticancer drug targets which have been studied intensively in the past few decades. Although several drugs have been approved in this field, they are still limited to a subset of hematological malignancies (in particular T-cell lymphomas), with therapeutic potential not fully realized and the drug-resistance occurred after a certain period of use. To maximize the therapeutic potential of these classes of anticancer drugs, and to extend their application to solid tumors, numerous combination therapies containing an HDACi and an anticancer agent from other mechanisms are currently ongoing in clinical trials. Recently, dual targeting strategy comprising the HDACs component has emerged as an alternative approach for combination therapies. In this perspective, we intend to gather all HDACs-containing dual inhibitors related to cancer therapy published in literature since 2015, classify them into five categories based on targets' biological functions, and discuss the rationale why dual acting agents should work better than combinatorial therapies using two separate drugs. The article discusses the pharmacological aspects of these dual inhibitors, including in vitro biological activities, pharmacokinetic studies, in vivo efficacy studies, as well as available clinical trials. The review of the current status and advances should provide better analysis for future opportunities and challenges of this field.

Introduction

Mutations, deregulated expression, and aberrant recruitment of epigenetic regulators are recognized as important contributors to the onset and maintenance of many types of human tumors. Among these regulators are epigenetic writers (such as DNA methyltransferases and histone acetylases or HATs), readers (such as bromodomain-containing proteins), and erasers (such as histone deacetylases or HDACs), all play crucial roles in the tumor pathological development. Particularly, chromatin remodeling regulators HDACs have received intensive studies in the past few decades, evidenced by the numbers from both scientific publications and clinical trials. Quick survey of literature reports on HDACs field using the SciFinder ® search engine reveals that the publication (papers and patents) number dramatically increases from 200 in the year 1999 to 2200 in the year 2019. As of today, more than 700 clinical trials involving the use of HDACs inhibitors are listed in the clinicaltrials.gov website, of which 200 trials are in the active or recruiting stage [1].

HDACs are a family of enzymes that catalyze the deacetylation of lysine residues of both histone and non-histone protein substrates [START_REF] Franci | Targeting epigenetic networks with polypharmacology: a new avenue to tackle cancer[END_REF]. There are eighteen human HDACs enzymes, which can be divided into four different categories: class I (HDACs 1,2,3,8), class II (HDACs 4,5,6,7,9,10), class III (Sirtuins 1,2,3,4,5,6,7) and class IV (HDAC 11). The class III HDACs enzymes are NAD + dependent while the others belong to zinc dependent metal enzymes [START_REF] Dallavalle | Development and therapeutic impact of HDAC6selective inhibitors[END_REF][START_REF] Chang | Chidamide, a novel histone deacetylase inhibitor, displays potent antitumor activity against MDS cells mainly through JAK2/STAT3 signaling inhibition[END_REF].

The expression levels of HDACs are usually higher in tumor cells than in normal cells. For instance, the following HDACs subtypes are found to be highly expressed in certain tumors: HDAC1 (gastric, lung, esophageal, colon, prostate, and breast cancers), HDAC2 (colorectal, cervical, and gastric cancers), HDAC3 (colon and breast tumors), HDAC6 (mammary tumors), HDAC8 (neuroblastoma), and HDAC11 (rhabdomyosarcoma).

Inhibition of HDACs can lead to pleiotropic effects on cellular signaling and transcription, including cell death, differentiation, autophagy, and enhancement of immunogenicity. The pharmacology of HDACs inhibitors (HDACi) has been clearly established and validated in clinic for cancer therapy. To date, five drugs are approved for the treatment of various types of lymphoma: vorinostat (SAHA), romidepsin (FK-228), belinostat (PXD-101), tucidinostat, and panobinostat (LBH-589). All of them belong to pan-HDACs inhibitors (Fig. 1) [START_REF] Song | A novel class of anthraquinone-based HDAC6 inhibitors[END_REF][START_REF] Zou | Characterization of the two catalytic domains in histone deacetylase 6[END_REF][START_REF] Liu | Structural biology: HDAC6 finally crystal clear[END_REF].

<insert Figure 1> Several excellent reviews have been published in recent years regarding to HDACi in cancer therapy [START_REF] Yoon | HDAC and HDAC inhibitor: from cancer to cardiovascular diseases[END_REF][START_REF] Newbold | How do tumor cells respond to HDAC inhibition?[END_REF][START_REF] Eckschlager | Histone deacetylase inhibitors as anticancer drugs[END_REF][START_REF] Zwergel | Application of small epigenetic modulators in pediatric medulloblastoma[END_REF][START_REF] Abbass | Recent perspectives of anticancer histone deacetylase inhibitors[END_REF][START_REF] Hamze | How do we improve histone deacetylase inhibitor drug discovery?[END_REF][START_REF] Rana | Understanding failure and improving treatment using HDAC inhibitors for prostate cancer[END_REF][START_REF] Kirsanov | Current approaches for personalized therapy of soft tissue sarcomas[END_REF][START_REF] Damaskos | Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer[END_REF][START_REF] Zwergel | Emerging approaches for histone deacetylase inhibitor drug discovery[END_REF]. In addition, HDACi as a potential treatment for other diseases such as fibrotic diseases [START_REF] Lyu | HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis[END_REF], multiple sclerosis [START_REF] Gray | Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis[END_REF], fatty liver diseases [START_REF] Bayoumi | The epigenetic drug discovery landscape for metabolic-associated fatty liver disease[END_REF], and aging [START_REF] Mcintyre | From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs[END_REF] have also been reported.

The structure of a typical HDACi consists of three key components: the cap group (acts as surface binding, Cap), the linker, and the pharmacophore (zinc-binding group, ZBG) (1, Fig. 1). The Cap portion, which accounts for the affinity gain through hydrophobic interaction with protein, can be large or small in size, and can modulate the selectivity of the HDACs subtype.

The linker is typically linear and hydrophobic as well. For example, straight carbon chain, transdi-substituted olefin or di-substituted phenyl or heteroaryl are often used as the linker. Most of the ZBGs (pharmacophore or warhead) are hydroxamic acid or its corresponding prodrugs, and to less extent ZBGs can also be acyl aniline, cyclic tetrapeptides, thiol, and aliphatic carboxylic acids, or their isosteric replacements [START_REF] Kim | HDAC6 inhibitor blocks amyloid beta-induced impairment of mitochondrial transport in hippocampal neurons[END_REF][START_REF] Kawaguchi | The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress[END_REF][START_REF] Parmigiani | HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation[END_REF].

As mentioned above, five HDACi approved drugs are all for hematological malignancies. Despite many clinical trials using a single agent of HDACi have been conducted for solid tumors, none of them are effective. To overcome the drug resistance development as well as to expand HDACs inhibitors' therapeutic potential for solid tumors, the combination strategy [START_REF] Zsakai | Targeted drug combination therapy design based on driver genes[END_REF][START_REF] Kummar | Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements[END_REF] is currently being investigated in the clinic. Synergistic and enhancement effects using the combination of an HDACi and a chemotherapy agent or targeted drug have been clearly demonstrated in both in vitro and in vivo studies [START_REF] Santo | Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma[END_REF][START_REF] Huang | Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models[END_REF]. Particularly encouraging, a recent phase III trial reveals that the combination of tucidinostat (chidamide) with exemestane improves progression-free survival in patients with advanced HR + and HER2 -breast cancer compared to the exemestane treatment group [START_REF] Jiang | Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial[END_REF][START_REF] Suraweera | Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi[END_REF].

Dual inhibitors of HDACs and one additional cancer-related target

Despite the success and promise in cancer treatment paradigms, an agent aiming at a single molecular mechanism (or pathway) faces limitations and obstacles, due to the compensation of defense mechanism by cancer cells, the complexity of tumor cell alterations, and the redundancy of survival pathways. The combination therapy has become a major trend in anti-cancer therapy, owing to its capability of both enhancing the efficacy and delaying or retarding the resistance. However, the combination therapy also faces several challenges yet to be addressed. Firstly, it has unpredictable drug-drug interactions between the two molecular entities. Secondly, the combination treatment might exacerbate the adverse effects of two agents.

Thirdly, the pharmacokinetics complexity needs to be taken into consideration. Lastly, it could involve much higher developmental costs and significantly more clinical trial efforts. Thus, dual or multi-targeting drug strategy has emerged as an alternative approach in recent years [START_REF] Musso | Perspectives in the development of hybrid bifunctional antitumour agents[END_REF].

Multi-targeting agents are capable of simultaneous intervention of two or more different biological targets (enzymes or signaling pathways) crucial for cancer progression. These agents were typically discovered through serendipity or screening in the early days. As the knowledge of molecular pathology of cancer deepens, scientists start the rational design of single agents, and use these agents on purposely to act on two (or more) different biological targets (or pathways) known to exhibit synergistic effects in the combination studies. Previous research studies in this field have been reviewed by several research groups [START_REF] Abbass | Recent perspectives of anticancer histone deacetylase inhibitors[END_REF][START_REF] Fu | Designing multi-targeted agents: an emerging anticancer drug discovery paradigm[END_REF][START_REF] Luan | Kinase and histone deacetylase hybrid inhibitors for cancer therapy[END_REF][START_REF] Schobert | Multimodal HDAC inhibitors with improved anticancer activity[END_REF][START_REF] Sangwan | HDAC as onco target: reviewing the synthetic approaches with SAR study of their inhibitors[END_REF]. Some of those reviews included dual targeting agents containing HDACi pharmacophore (being called as HDACs hybrid molecules), with the emphasis on other aspects such as medicinal chemistry. Due to the rapid development of this field and the increasing number of publications, summarizing the up-to-date advances not been covered in previous reviews is extremely necessary.

The accumulating knowledge of HDACi SAR in literature has revealed that the Cap can tolerate diverse structures while still maintaining a reasonably good in vitro activity. To design a dual inhibitor of HDACs and a target (kinases, epigenetic targets, other enzymes, receptors, and miscellaneous), one could simply swap the Cap with structure fragment from an inhibitor of the designated target (Fig. 2). The key is to identify a suitable attaching point where the HDACs pharmacophore side chain can be installed, and ensuring such chemical attachment with little to no influence on the biological activity against the original target. Additionally, an optimal attaching point should also allow the synthetic feasibility of the designed molecule. All these key factors should be taken into consideration while designing a dual targeting agent.

<insert Figure 2>

Dual inhibitors of HDACs and protein kinases

Drug discovery targeting protein kinases has been one of major focuses for pharmaceutical industries in the last few decades, and the efforts have produced fruitful success.

By January 2020, the US FDA has approved 52 small molecule protein kinase inhibitors for various human diseases [START_REF] Roskoski | Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update[END_REF]. As many as 46 of them are used in the treatment of neoplastic diseases (41 against solid tumors, 8 against non-solid tumors, and some drugs are used against both tumor types). Due to the tremendous efforts and fruitfulness in this field, protein kinases class has been considered by scientific community as one of the earliest target classes to be cotargeting with HDACs. In this session, we will discuss these dual targeting agents involving HDACs and protein kinases.

Dual inhibitors of HDACs and CDKs

Cyclin-dependent kinases (CDKs) are heterodimeric protein kinases that play a central role in the control of cell cycle progression. These kinases function through phosphorylation of well-defined enzymatic and structural targets, and are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells [START_REF] Morgan | The Cell Cycle: Principles of Control (1 st Edition)[END_REF]. The US FDA approved the following three drugs targeting CDKs: palbociclib (2015), abemaciclib (2017), and ribociclib (2017). Conceptual design of a dual inhibitor targeting both HDACs and CDKs is supported by several scientific publications. In 2010, Keshelava and co-workers reported that the combination of vorinostat (SAHA) and flavopiridol (a pan-CDKs inhibitor) was significantly more cytotoxic to neuroblastomas with p53 LOF (loss of function) via TP53 mutations or p14ARF deletion [START_REF] Huang | Combination of vorinostat and flavopiridol is selectively cytotoxic to multidrug-resistant neuroblastoma cell lines with mutant TP53[END_REF].

Using a genomic approach, Bild and co-workers predicted that the combination of SAHA and palbociclib could have synergistic effects for the treatment of breast cancer. They then subsequently validated this prediction in an in vitro study [START_REF] Soldi | A genomic approach to predict synergistic combinations for breast cancer treatment[END_REF]. Furthermore, Jochemsen and coworkers reported that the combination of quisinostat (a clinical pan-HDACs inhibitor developed by JNJ) and flavopiridol not only showed synergistic reduction effects of cell viability against several melanoma cell lines including BRAF v600E mutant melanoma [START_REF] Heijkants | Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma[END_REF], but also caused tumor regression in cutaneous melanoma PDX mice without increase of adverse effects.

The above scientific supports prompted several research groups to design and synthesize dual CDKs-HDACs inhibitors. In a 2017 patent application, Zhang and co-workers [START_REF] Zhang | Heterocycles useful as anti-cancer agents[END_REF] disclosed a series of dual CDKs-HDACs inhibitors derived from palbociclib and SAHA. The representative compound 6 shows potent inhibitory activities against CDK4/6 and HDAC1 (IC50 for CDK4 and CDK6: <10 nM and <25 nM; IC50 for HDAC1: <50 nM). No further characterization for those dual inhibitors was given. In 2018, Xiang et al [START_REF] Huang | Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling[END_REF][START_REF] Zhao | Enhancement of histone deacetylase inhibitor sensitivity in combination with cyclin-dependent kinase inhibition for the treatment of oral squamous cell carcinoma[END_REF][START_REF] Li | Discovery of N1-(4-((7-Cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)-N8hydroxyoctanediamide as a novel inhibitor targeting cyclin-dependent kinase 4/9 (CDK4/9) and histone deacetlyase1 (HDAC1) against malignant cancer[END_REF] reported two series of dual CDKs-HDACs inhibitors, one derived from abemaciclib and SAHA, and the other derived from ribociclib and SAHA. Compound 7, a representative compound derived from abemaciclib series, shows potent inhibitory activities against both CDK4 and HDAC1 (IC50 for CDK4: 1.2 nM; HDAC1: 26 nM). In a cellular assay, compound 7 induces cell apoptosis and G1-phase arrest in various breast and ovarian cancer cells (IC50: 15.8-44 nM in the following cell lines: 4T1, MDA-MB-468, MDA-MB-231, SK-OV-3, OVCAR-5, and H460). Importantly, compound 7 significantly inhibits tumor growth in breast cancer homograft and xenograft mice with low toxicity. Compound 8, a representative compound derived from ribociclib series, not only shows potent inhibitory activities against both CDK4 and HDAC1 (IC50: 8.8 nM and 2.2 nM respectively), but also exhibits greater anti-proliferative effects against 9 cancer cell lines (IC50 ranging from 1.11 to 3.78 µM) than ribociclib or SAHA separately. In in vivo studies, compound 8 is orally bioavailable (%F = 18.4%), and significantly inhibits tumor growth in 4T1 xenograft mice at 130 mg/kg dose without causing obvious toxicity (indicated by body weight decrease). In 2019, Gan et al [START_REF] Yu | Discovery of novel 9H-purin derivatives as dual inhibitors of HDAC1 and CDK2[END_REF] reported a series of dual CDKs-HDACs inhibitors derived from roscovitine (an investigational drug of CDKs inhibitor) and panobinostate. The representative compound 9 exhibits potent inhibitory activities against both CDK2 and HDAC1 and effectively induces apoptosis of three cancer cell lines (A549, HepG2, and CAL-148). Yuan et al [START_REF] Cheng | Discovery of novel cyclin-dependent kinase (CDK) and histone deacetylase (HDAC) dual inhibitors with potent in vitro and in vivo anticancer activity[END_REF] reported a series of dual CDKs-HDACs inhibitors derived from a known CDK1/2 inhibitor AT7519 [START_REF] Chen | A phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC clinical trials group IND 177[END_REF]. An HDACs pharmacophore (hydroxamic acid) side chain was attached to AT7519's phenyl portion, a region known to expose to the solvent region. Thus, the most active analog 10 from the series could arrest cell cycle in G2/M phase and promoted apoptosis in A75, HCT116, H460, and Hela cells. which was associated with increasing the intracellular reactive oxygen species (ROS) levels. In in vivo studies, compound 10 showed very good ip (intraperitoneal) bioavailability (%F = 63.6%) in ICR mice, and significantly inhibited tumor growth in HCT-116 xenograft mice upon 25 mg/kg once daily (qd) ip dosing for 21 days (Table 1).

<insert Table 1>

Dual inhibitors of HDACs and CK2

Casein kinase 2 (CK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, circadian rhythm regulation, and other cellular processes. High expression levels of CK2 have been associated with numerous solid tumors and hematologic malignancies [START_REF] Ahmad | Protein kinase CK2 -A key suppressor of apoptosis[END_REF]. The most advanced CK2 inhibitor is silmitasertib (CX-4945) [START_REF] Chon | The casein kinase 2 inhibitor, CX-4945, as an anticancer drug in treatment of human hematological malignancies[END_REF], which is currently in several clinical trials for treatment of multiple myeloma, kidney cancer, medulloblastoma, and advanced solid tumors. In January 2017, it was granted orphan drug status by the US FDA for advanced cholangiocarcinoma. There is no approval drug for CK2 inhibitor.

Three different series of dual CK2-HDACs inhibitors reported to date are all from de Pascual-Teresa's group (Table 2) [START_REF] Purwin | Design and synthesis of novel dual-target agents for HDAC1 and CK2 inhibition[END_REF][START_REF] Martínez | Multitarget anticancer agents based on histone deacetylase and protein kinase CK2 inhibitors[END_REF][START_REF] Rangasamy | New dual CK2/HDAC1 inhibitors with nanomolar inhibitory activity against both enzymes[END_REF]. Compound 11 was derived from TBB [START_REF] Sarno | Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ('casein kinase-2')[END_REF] and HDAC pharmacophore hydroxamic acid using click chemistry. Despite the weaker CK2α activity comparing to TBB (62% inhibition @50 µM vs IC50 value of 800 nM by TBB) and weaker HDAC1 activity comparing to SAHA (IC50: 2.2 µM vs 33 nM), compound 11 exhibits significantly greater anti-proliferative effects against Jurkat cell line (human leukemia) than its parent TBB (LC50: 2.5 µM vs 20 µM). Although the LC50 value of 11 is identical to that of SAHA, its proapoptotic activity is significantly higher, indicated by quantitative annexin V/PI apoptosis assay using flow cytometry. These results suggest synergistic and beneficial effects of inducing proapoptotic activities using a dual CK2-HDACs inhibitor. Compound 12, a hybrid molecule derived from DMAT [START_REF] De | Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT[END_REF] and SAHA, shows moderate inhibitory activities against CK2 and HDAC1 and good anti-proliferative effects against 7 tumor cells (IC50 values ranging from 2 to 9 µM). Derived from clinical candidate silmitasertib and approved drug SAHA, compound 13 exhibits greater inhibitory activities against both CK2 and HDACs compared to its parents silmitasertib and SAHA (IC50 for CK2: 1.7 nM vs 1.8 nM of silmitasertib; IC50 for HDAC1: 3.3 nM vs 33 nM of SAHA; IC50 for HDAC6: 13 nM vs 33 nM of SAHA).

Unfortunately, the excellent enzymatic activities of 13 did not transfer into good antiproliferative effects against 4 different cancer cell lines. This might be due to the low permeability of compound 13 in cells.

<insert Table 2>

Dual inhibitors of HDACs and RTKs

Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Inhibition of the kinase domain of RTKs has been validated as a strategy for cancer therapy [START_REF] Tiash | Growth factor receptors: promising drug targets in cancer[END_REF]. The US FDA has approved several small molecule drugs targeting the kinase domain of Rs, including fibroblast growth factor receptors (FGFRs), epidermal growth factor receptor (EGFR), and vascular endothelial growth factors (VEGFRs). For example, nintedanib (targeting FGFR1/2/3) was approved for treatment of idopathic pulmonary fibrosis in 2014, while erdafitinib (targeting FGFR1/ [START_REF] Luan | Kinase and histone deacetylase hybrid inhibitors for cancer therapy[END_REF][START_REF] Abbass | Recent perspectives of anticancer histone deacetylase inhibitors[END_REF][START_REF] Fu | Designing multi-targeted agents: an emerging anticancer drug discovery paradigm[END_REF]. More recently, a rational designed dual EGFR and HDACs inhibitor compound 14 (derived from osimertinib and SAHA) shows interesting biological activities (Table 3) [START_REF] Dong | Design, synthesis and biological evaluation of novel osimertinib-based HDAC and EGFR dual inhibitors[END_REF]. Despite having weak inhibitory activities against both EGFR WT and EGFR T790M , compound 14 exhibits better anti-proliferative effects against several cancer cell lines (IC50 values ranging from 0.23 to 1.85 µM for the following cells: MDA-MB-231, MDA-MB-468, KG-1, HT-29, and HeLa) compared to its parent osimertinib. As reported by Hu et al [START_REF] Liu | Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold[END_REF], the dual FGFR1-HDACs inhibitor 15 exhibits moderate inhibitory activities against FGFR1 and HDAC1 (64% and 59% inhibition at 1 µM concentration, respectively) and potent inhibitory activity against HDAC6 (IC50: 34 nM). No further pharmacological studies were reported. c-Met, also named tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is known as a RTK. After binding to its specific ligand hepatocyte growth factor (HGF), c-Met activates a wide range of different cellular signaling pathways, including those involved in cancer cell proliferation, survival, invasion, metastasis, and angiogenesis etc. The c-Met pathway is dysregulated in various cancers especially those associated with metastasis, and c-Met inhibition could effectively reduce c-Met signaling and metastatic phenotype in a range of preclinical models [START_REF] Hughes | Have clinical trials properly assessed c-Met inhibitors?[END_REF][START_REF] Parikh | Recent advances in the discovery of small molecule c-Met kinase inhibitors[END_REF]. Several c-Met inhibitors were advanced to various stages of clinical trials [START_REF] Rehman | MET inhibition in non-small cell lung cancer[END_REF].

In 2020, the first c-Met selective inhibitor capmatinib (INC280) was approved by the US FDA as a first-line treatment for non-small cell lung cancer (NSCLC) patients with the MET exon 14 skipping (METex14) mutation [64]. There are only a few series of dual c-Met-HDACs inhibitors reported to date. In 2017, Hu et al [START_REF] Lu | Design, synthesis, and biological evaluation of the first c-Met/HDAC inhibitors based on pyridazinone derivatives[END_REF] reported first dual c-Met-HDACs inhibitors based on a known c-Met inhibitor and tucidinostat. Compound 16 shows potent inhibitory activities against c-Met and HDAC1 (IC50 values are 0.71 and 38 nM respectively) [START_REF] Lu | Design, synthesis, and biological evaluation of the first c-Met/HDAC inhibitors based on pyridazinone derivatives[END_REF]. In cellular assays, compound 16 shows greater anti-proliferative effects against EBC-1 and HCT-116 cells than the parent tucidinostat. Compound 17 is a representative compound derived from crizotinib and SAHA [START_REF]Novel c-Met/HDAC dual-target inhibitor and its synthesis method for antitumor drug preparation[END_REF]. It potently inhibits c-Met and HDAC1/2 enzymatically. Compound 18 [START_REF] Hu | Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy[END_REF] has the same quinoline scaffold as compound 16, but with different side chains. It has a similar in vitro activity profile as compound 16, not only in enzymatic levels, but also in cellular levels.

However, comparing with an equimolar mixture of its parent compounds, SAHA and foretinib, compound 18 did not exhibit synergistic effect in inhibiting cancer cells proliferation. <insert Table 3>

Dual inhibitors of HDACs and JAKs

The Janus kinases (JAK1, JAK2, JAK3, and TYK2) are intracellular non-receptor tyrosine kinases. They play essential roles in the cell signaling pathway activated by a variety of cytokines and implicates in the pathogenesis of various cancer types [START_REF] Laurence | JAK kinases in health and disease: an update[END_REF]. Activation of JAKs by different cytokines results in phosphorylation and dimerization of the STAT (signal transducer and activator of transcription) proteins, which further translocate to the nucleus and activate gene transcription [START_REF] O'shea | JAK and STAT signaling molecules in immunoregulation and immune-mediated disease[END_REF]. The JAK-STAT signaling axis is associated with diverse biological functions including inflammation, immune function, and hematopoiesis [START_REF] Shuai | Regulation of JAK-STAT signalling in the immune system[END_REF][START_REF] Clark | Discovery and development of janus kinase (JAK) inhibitors for inflammatory diseases[END_REF]. Thus, JAKs are validated therapeutic targets for autoimmune diseases such as rheumatoid arthritis, myelofibrosis, and polycythemia vera. To date, there are four JAKs inhibitors approved by the US FDA, all for the treatment of diseases related to the immune system. The potential treatment for cancers using a JAKs inhibitor is still under clinical investigation. For example, itacitinib (INCB039110) is in various stages of clinical trials for advanced HCC (hepatocellular carcinoma), lymphoma, and other solid tumors [72]. Conceptual design of dual inhibitors targeting both JAKs and HDACs is supported by several scientific publications. In 2013, Radimerski and co-workers reported that the combination of ruxolitinib (a JAKs inhibitor approval drug) and panobinostat resulted in enhanced efficacy in mouse models of JAK2 V617F -driven disease compared to corresponding single agents [START_REF] Evrot | JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2 V617F -driven disease[END_REF]. In addition, the combination of HDACs inhibitor pracinostat (SB939) and JAK2 inhibitor pacritinib demonstrated synergistic effects on the reduction of tumor growth and the normalization of plasma cytokines/growth factors/chemokines [START_REF] Novotny-Diermayr | The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML[END_REF]. Furthermore, Wang and co-workers reported that the combination of panobinostat and JAK2 inhibitor fedratinib (TG101209) could reduce JAK2 V617F levels and could produce synergistic cytotoxic effects against human myeloproliferative neoplastic cells [START_REF] Wang | Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells[END_REF].

These synergy effects discussed above provide the scientific rationale for medicinal chemistry design of dual JAKs-HDACs inhibitors. Dymock's group published three articles and one patent describing three series of dual JAKs-HDACs inhibitors [START_REF] Yang | Design and synthesis of janus kinase 2 (JAK2) and histone deacetlyase (HDAC) bispecific inhibitors based on pacritinib and evidence of dual pathway inhibition in hematological cell lines[END_REF][START_REF] Dymock | Preparation of dioxatriazatetracycloheptacosadecaene derivatives for use as JAK and HDAC dualinhibitors[END_REF][START_REF] Yao | Design and synthesis of ligand efficient dual inhibitors of janus kinase (JAK) and histone deacetylase (HDAC) based on ruxolitinib and vorinostat[END_REF][START_REF] Chu-Farseeva | Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat[END_REF] The anti-proliferative activities of 20 against solid tumor cells are greater or comparable to the activities of SAHA, and are significantly better than those of ruxolitinib (IC50 0.79 to 2.41 µM vs >10 µM). Unfortunately, compound 20 has very poor oral bioavailability in Wistar rats (1.4%), and might be served as a tool molecule rather than a development candidate. Derived from JAK2-selective inhibitor XL019 (a terminated clinical candidate due to CNS penetration and related side effects), compound 21 exhibits potent inhibitory activities against JAK2, HDAC1, and HDAC6 (IC50 values are 3.1, 56, and 1.2 nM respectively). In cellular assays, compound 21 exhibits better anti-proliferative effects against four solid tumor cells (HCT-116, MDA-MB-231, MCF-7, and PC-3) compared to XL019, and better or similar activities compared to SAHA.

Mechanistic studies reveal that the apoptosis is responsible for tumor cell death, and the inhibition of both HDACs and JAK-STAT pathways contributes to the greater in vitro potency.

It is worth mentioning that compound 21 shows less CNS penetration compared to XL019 and is expected to have better safety profile. In 2018, Yu et al [START_REF] Ning | Macrocyclic compounds as anti-cancer agents: design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2[END_REF] reported multi-targeting JAKs-FLT3-HDACs inhibitors derived from zotiraciclib (SB1317) and SAHA. The representative compound 22 shows potent inhibitory activities against JAK2, FLT3, and HDAC (IC50 values are 686, 87, and 87 nM respectively). In cellular assays, compound 22 exhibits potent antiproliferative effects against several leukemia and solid tumors cells (Table 4). In 2018, Huang et al [START_REF] Huang | Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) dual inhibitors as a novel strategy for the combinational treatment of leukemia and invasive fungal infections[END_REF] reported that the combination of momelotinib (CYT-387) and SAHA in 1:1 ratio exhibits greater antiproliferative activity against HL60 and K562 cells than that from either of the single agent alone. Based on the synergistic results, they designed and synthesized a series of dual JAKs-HDACs inhibitors derived from momelotinib and SAHA. The representative compound 23 is a potent JAK2/HDAC6-selective dual inhibitor (IC50 values for JAK2, HDAC1, HDAC3, and HDAC6 are 8, 1100, 234, and 46 nM respectively). In cellular assays, compound 23 induces cell apoptosis and G2/M-phase arrest in HEL cells (IC50: 0.34 µM), more potent than the combination of momelotinib and SAHA (1:1). In addition, compound 23 also shows antiproliferative effects against HL-60 and K562 cells (IC50: 1.5 and 8.7 µM respectively). When administrated at a dose of 10 mg/kg to SD rats intraperitoneally, compound 23 shows good plasma exposure (AUC of 4470 h*ng/mL). In AML and HEL xenograft mice, compound 23 causes statistically significant inhibition of tumor growth upon ip dosing of 10 mg/kg for 21 days.

Interestingly, the combination of compound 23 and fluconazole (FLC, a first-generation triazole antifungal medication) exhibits excellent synergistic antifungal effects against the FLC-resistant C. albicans strain 0304103 in the in vivo studies. Specifically, ICR mice treated with the combination of compound 23 (5 mg/kg) and FLC (1 mg/kg) had significant improvement in survival rate without signs of toxicity. This is the first example of a small molecule possessing both anti-cancer (AML) and anti-fungal (against FLC-resistant infection) efficacy in vivo. In 2019, Zhang et al [START_REF] Liang | Discovery of novel ianus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors for the treatment of hematological malignancies[END_REF] reported a series of dual JAKs-HDACs inhibitors based on their previously reported N 2 -(1H-pyrazol-4-yl)pyrimidine-2,4-diamine scaffold [START_REF] Liang | Design, synthesis, and antitumor evaluation of 4-Amino-(1H)-pyrazole derivatives as JAKs inhibitors[END_REF]. Among those analogs reported, compound 24 exhibits pan-JAKs and HDAC6-selective inhibitory activities (IC50 values for JAK1-3 and TYK2 ranging from 4 to 49 nM; IC50 values for HDAC6, HDAC2, and HDAC8 are 14, 120, and 2470 nM respectively). In cellular assays, compound 24 induces cell apoptosis and exhibits anti-proliferative effects against several tumor cells (IC50 values for HEL bearing the JAK2 V617F mutation, K562, MOLT4, and Jurkat cells are 0.09, 0.49, 0.08, and 0.06 µM respectively). Dual inhibitors reported in this article exhibit more potent than the combination of ruxolitinib and SAHA in vitro. Unfortunately, the oral bioavailability of compound 24 is very poor (<1%), despite its ip bioavailability is good. Thus, the in vivo studies of compound 24 were conducted in HEL xenograft mice using ip dosing (100 mg/kg, qd, for 16 consecutive days), and moderate anti-tumor efficacy and good safety profiles (no significant body weight loss and no observable signs of toxicity) were obtained.

<insert Table 4>

Dual inhibitors of HDACs and PI3Ks (and/or mTOR)

The phosphatidylinositol-3-kinases (PI3Ks)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are crucial to many aspects of cell growth and survival, in both physiological and pathological conditions [START_REF] Vanhaesebroeck | PI3K signalling: the path to discovery and understanding[END_REF][START_REF] Porta | Targeting PI3K/Akt/mTOR signaling in cancer[END_REF][START_REF] Yang | Targeting PI3K in cancer: mechanisms and advances in clinical trials[END_REF]. Thus, targeting these pathways has been extensively studied from mechanism of action to preclinical experiment to clinical investigation.

Inhibitors approved for cancer treatment by the US FDA are alpelisib (BYL-719, PI3Kαselective inhibitor), copanlisib (BAY 80-6946, pan-PI3K inhibitor), and duvelisib (IPI-145, PI3Kδ-selective inhibitor). Among all kinases, PI3Ks class was probably the first kinase class investigated as dual inhibitor with HDACs. The synergistic anti-tumor effects have been reported using the combination of an HDACi and a PI3Ks inhibitor as well as using a dual PI3Ks-HDACs inhibitor [START_REF] Qian | Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling[END_REF][START_REF] Pei | HDAC and PI3K antagonists cooperate to inhibit growth of MYCdriven medulloblastoma[END_REF][START_REF] Yoshioka | Combination of a novel HDAC inhibitor OBP-801/YM753 and a PI3K inhibitor LY294002 synergistically induces apoptosis in human endometrial carcinoma cells due to increase of bim with accumulation of ROS[END_REF][START_REF] Mosleh | Pan-HDAC inhibitor panobinostat, as a single agent or in combination with PI3K inhibitor, induces apoptosis in APL cells: an emerging approach to overcome MSC-induced resistance[END_REF][START_REF] Meng | Enhanced efficacy of histone deacetylase inhibitor panobinostat combined with dual PI3K/mTOR inhibitor BEZ235 against glioblastoma[END_REF]. Indeed, the first-in-class dual PI3Ks-HDACs inhibitor fimepinostat (CUDC-907) [START_REF] Li | CUDC-907 enhances TRAIL-induced apoptosis through upregulation of DR5 in breast cancer cells[END_REF][START_REF] Okabe | Effect of dual inhibition of histone deacetylase and phosphatidylinositol-3 kinase in Philadelphia chromosome-positive leukemia cells[END_REF][START_REF] Li | Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia[END_REF][START_REF] Chen | CUDC 907 blocks multiple pro-survival signals and abrogates microenvironment protection in CLL[END_REF][START_REF] Pal | Dual HDAC and PI3K inhibition abrogates NFκB-and FOXM1-mediated DNA damage response to radiosensitize pediatric high-grade gliomas[END_REF][START_REF] To | CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance[END_REF][START_REF] Kotian | Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 inhibits thyroid cancer growth and metastases[END_REF][START_REF] Sun | Dual HDAC and PI3K inhibitor CUDC-907 downregulates MYC and suppresses growth of MYC-dependent cancers[END_REF][START_REF] Younes | Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial[END_REF][START_REF] Wu | Human ATP-binding cassette transporter ABCG2 confers resistance to CUDC-907, a dual inhibitor of histone deacetylase and phosphatidylinositol 3-kinase[END_REF] developed by Curis, Inc. is the most advance compound in this field, and has entered into various stages of clinical trials. This review focuses dual PI3Ks-HDACs inhibitors reported in the literature after 2015. Compound 25 (Table 5) [START_REF] Chen | Design, synthesis, and preclinical evaluation of fused pyrimidine-based hydroxamates for the treatment of hepatocellular carcinoma[END_REF], a dual inhibitor derived from pyrimidine scaffold, exhibits balanced pan-inhibition across PI3Ks subtypes and selective inhibition against HDAC1, 2, 3, 6, and 10. In cellular assays, compound 25 shows greater antiproliferative effects against several cancer cells (leukemia, lymphomas, and liver cancers) than SAHA or sorafenib alone. These cellular activities have been successfully transferred to in vivo efficacy in HCC xenograft mice. Importantly, compound 25 has good oral bioavailability (%F = 18%) in rats at 150 mg/kg dose to rats. Compound 26 [START_REF] Chen | Development of purine-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities[END_REF], a close analog of fimepinostat, exhibits weaker inhibitory activity against PI3Ks (IC50 >1 µM) compared to fimepinostat, but remains potent and balanced inhibitory activities against all HDACs subtypes. Despite of the weaker activity against PI3Ks, compound 26 shows greater anti-proliferative effects against MV4-11 and HCT-116 cells than fimepinostat and SAHA alone. In the in vivo studies, compound 26 has good oral bioavailability in dog (%F = 41.8%), and shows good antitumor efficacy in various tumor cells xenograft mice models. Compound 27 [START_REF] Wu | Design, synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-c]quinazoline derivatives as novel phosphatidylinositol 3-kinase and histone deacetylase dual inhibitors[END_REF], a dual PI3K-HDACs inhibitor derived from copanlisib and SAHA, shows excellent inhibitory activities against HDACs and PI3Ks, and potent anti-proliferative effects against several tumor cells.

Compound 28 [START_REF] Zhang | Design, synthesis, and biological evaluation of 4 methyl quinazoline derivatives as anticancer agents simultaneously targeting phosphoinositide 3 kinases and histone deacetylases[END_REF], derived from the HDACs pharmacophore and a quinazoline scaffold of known PI3K inhibitors [START_REF] Lin | Discovery and optimization of 2 amino-4methylquinazoline derivatives as highly potent phosphatidylinositol 3 kinase inhibitors for cancer treatment[END_REF], possesses slightly different selectivity profiles of PI3Kδ and HDACs in enzymatic levels compared to clinical candidate fimepinostat. For instance, compound 28 is a potent PI3Kδ-selective inhibitor with 5 to 12-fold selectivity over other PI3K subtypes (IC50 for PI3Kδ: 8.1 nM), while fimepinostat exhibits PI3Kβ-selectivity (IC50 for PI3Kβ: 16 nM, 4 to 23-fold over other PI3K subtypes). Both compound 28 and fimepinostat have similar profiles of good selectivity against Class I (HDAC1, HDAC2, HDAC3, HDAC8) and Class IIB (HDAC6) HDACs. Interestingly, compound 28 has much weaker inhibitory activity against HDAC4 and HDAC11 than fimepinostat. Since the inhibition of HDAC4 and HDAC11 is known to cause potential side effects, compound 28 might have better safety profiles than fimepinostat [START_REF] Yanginlar | HDAC11 is a regulator of diverse immune functions[END_REF][START_REF] Boutillier | The dark side of HDAC inhibition in ALS[END_REF]. In the cellular assays, compound 28 shows good anti-proliferative effects against several hematologic and solid tumor cells, although its anti-proliferative effects are relatively less potent than fimepinostat. In the pharmacokinetic study, compound 28 is orally bioavailable in mice (%F = 4.2%). Furthermore, compound 28 significantly inhibits tumor growth in HCT-116 and HGC-27 xenograft mice upon p.o. dosing (150 mg/kg, TGI: 45.8%) or ip dosing (30 mg/kg, TGI: 62.6%). PI-103 [START_REF] Raynaud | Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941[END_REF] is a potent PI3K and mTOR inhibitor derived from clinical candidate GDC-0941. Fraga et al [START_REF] Rodrigues | Design, synthesis and pharmacological evaluation of first-in-class multitarget N-acylhydrazone derivatives as selective HDAC6/8 and PI3Kα inhibitors[END_REF] reported a series of PI3Kα and HDAC6/8selective dual inhibitors based on the rational design from PI-103 and LASSBio-1911 [START_REF] Rodrigues | Design, synthesis, and pharmacological evaluation of novel N-acylhydrazone derivatives as potent histone deacetylase 6/8 dual inhibitors[END_REF].

Thus the representative compound 29 exhibits potent inhibitory activities against PI3Kα/β/δ and HDAC6/8 in enzymatic levels (IC50 values are 46, 73, 72, 15, and 68 nM, respectively). Recently Grewal et al [START_REF] Thakur | Design, synthesis and biological evaluation of quinazolin-4-one based hydroxamic acids as dual PI3K/HDAC inhibitors[END_REF] reported compound 30 as a PI3Kγ/δ-and HDAC6-selective dual inhibitor.

The target engagement of PI3Kδ and HDAC6 by 30 was validated in MV411 cells in a cellular thermal shift assay (CETSA). However, this compound has poor oral bioavailability (%F = 0.7%).

As early as 2012, Yu et al [START_REF] Shao | Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo[END_REF] observed the synergistic antitumor effects using the combination of an mTORi and an HDACi, both in vitro in HCC cells and in vivo in a HCC PDX (patient-derived xenograft) mice model. Despite of strong scientific evidence from both preclinical and clinical studies, the discovery of dual inhibitors targeting mTOR and HDACs progresses slowly. Up to date, there is only one report regarding to dual mTOR-HDACs inhibitors. Compound 31 [START_REF] Chen | Discovery of novel dual histone deacetylase and mammalian target of rapamycin target inhibitors as a promising strategy for cancer therapy[END_REF] is a highly potent and selective inhibitor against mTOR and HDAC1/6 (IC50 values are 1.2, 0.19, and 1.8 nM respectively). The selectivity of mTOR over PI3Kα is greater than 416-fold. Molecular biology studies confirm that compound 31 upregulates acetylation of H3 and α-tubulin, and at the same time downregulates mTOR-related downstream signaling pathway. In MM1S xenograft mice, treatment using compound 31 exhibits comparable antitumor activity but fewer side effects compared to the treatment using combination SAHA and rapamycin. <insert Table 5>

Dual inhibitors of HDACs and Syk

Spleen tyrosine kinase (Syk), a non-receptor cytoplasmic tyrosine kinase primarily expressed in hematopoietic tissues, mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR).

Abnormal function of Syk has been implicated in several instances of hematopoietic malignancies. Fostamatinib is an FDA-approved Syk inhibitor for treatment of chronic immune thrombocytopenia. There are a number of clinical trials ongoing using fostamatinib alone or in combination for hematological malignancies and solid tumors such as ovarian cancer. To date, there is no report regarding the combination of an HDACi with a Syk inhibitor for cancer treatment in the literature. Compounds 32 and 33 (Table 6), the dual inhibitors in this class [START_REF] Zhang | Heterocyclic compound serving as SyK inhibitor and /or SyK-HDAC dual inhibitor[END_REF][START_REF] Zhang | Preparation of heterocyclic compound as Syk and /or Syk-HDAC dual inhibitor[END_REF], can serve as tool molecules in elucidating whether a synergy effect exists for cancer treatment.

<insert Table 6>

Dual inhibitors of HDACs and Bcr-Abl kinase

The fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22 results in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase. Such abnormality is often called as Philadelphia chromosome, which is responsible for more than 90% of chronic myelogenous leukemia (CML).

The US FDA has approved the following drugs for treatment of CML or AML: imatinib ( 2001

Dual inhibitors of HDACs and Raf kinase

Raf (acronym for rapidly accelerated fibrosarcoma) kinases are a family of three serine/threonine-specific protein kinases namely A-Raf, B-Raf, and C-Raf. Raf kinases are core components of the RAS-RAF-MEK-ERK signal transduction cascade, and are also involved in the mitogen-activated protein kinase (MAPK) cascade. Vemurafenib, dabrafenib, and encorafenib are three drugs targeting B-Raf approved by the US FDA. Zhu et al [START_REF] Chen | Design, synthesis and biological evaluation of novel benzoylimidazole derivatives as raf and histone deacetylases dual inhibitors[END_REF][START_REF] Geng | Discovery of novel phenoxybenzamide analogues as Raf/HDAC dual inhibitors[END_REF] reported two closely related series of dual Raf-HDACs inhibitors based on sorafenib scaffold, with slightly different ZBG. The representative compounds 35 and 36 (Table 8) exhibit similar in vitro activities in both enzymatic assay and cellular assays.

<insert Table 8>

Dual inhibitors of HDACs and other epigenetic target

Dual inhibitors of HDACs and BET

Bromodomain-containing proteins (BRDs) are a family of 46 proteins consisting of 61 modules. These BRDs recognize acetylated lysine residues in histones and serve as readers responsible for post-translational modulation. Among these proteins, BRD2, BRD3, BRD4 and BRDT belong to bromodomain and extra-terminal (BET) family [START_REF] Filippakopoulos | Targeting bromodomains: epigenetic readers of lysine acetylation[END_REF]. Like HATs (writers) and HDACs (erasers), BET (readers) are important epigenetic modulators, which control the expression of genes related to regulation of various physiological functions, including inflammation, apoptosis, cell proliferation, cell cycle, pancreatic β cell function, and adipogenesis [START_REF] Huang | Brd4 coactivates transcriptional activation of NF-κB via specific binding to acetylated RelA[END_REF][START_REF] Yang | Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression[END_REF][START_REF] Mochizuki | The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase[END_REF][START_REF] Denis | An emerging role for bromodomaincontaining proteins in chromatin regulation and transcriptional control of adipogenesis[END_REF]. Thus, targeting BET has been validated in preclinical studies for treatment of various diseases including cancers [START_REF] Arrowsmith | Epigenetic protein families: a new frontier for drug discovery[END_REF][START_REF] Dawson | Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia[END_REF][START_REF] Denis | Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation[END_REF][START_REF] Nicholls | ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies[END_REF]. To date, many BET inhibitors have been advanced to various stages of clinical trials: BMS-986158, birabresib (MK-8628), CPI-0610, mivebresib (ABBV-075), molibresib (I-BET762), and INCB-057643, etc [START_REF] Alqahtani | Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy[END_REF].

Conceptual design of dual inhibitor targeting both BET and HDACs is supported by several scientific publications. In 2014, Nilsson and co-workers [START_REF] Bhadury | BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma[END_REF] reported that BETi and HDACi could induce similar genetic and biological effects and the combination of these two synergistically led to the death of murine lymphoma induced by Myc overexpression. When coadministrating BRD4 antagonist JQ1 and histone deacetylases inhibitor panobinostat to the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells, the significant improvement of animals survival was observed indicating the synergistic effects [START_REF] Fiskus | Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells[END_REF]. In 2016, Geng and coworkers discovered that the feedback activation of leukemia inhibitory factor receptor (LIFR) signaling restrained the efficacy of HDACi in breast cancer while BRD4 inhibitor sensitized breast cancer to HDACi. This finding provides mechanistic foundation for breast cancer treatment using the combination of BRD4 inhibitor and HDACi [START_REF] Zeng | Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer[END_REF].

The above discoveries strongly support the design of a single small molecule targeting both BET and HDACs. In 2014, Prinjha et al [START_REF] Atkinson | The structure based design of dual HDAC/BET inhibitors as novel epigenetic probes[END_REF] reported compound 37 (Table 9), a potent dual BET-HDACs inhibitor structurally derived from I-BET295 and SAHA. This compound shows potent inhibitory activities against BRD4 and HDAC1 enzymatically (IC50 values are 50 and 250 nM respectively), and potent anti-proliferative effects against HL-60 and MV4-11 (IC50 values for 764 and 334 nM respectively) in cellular assays. In 2016, Chen et al [START_REF] Zhang | Targeting epigenetic reader and eraser: rational design, synthesis and in vitro evaluation of dimethylisoxazoles derivatives as BRD4/HDAC dual inhibitors[END_REF] reported a series of dual BRD4-HDACs inhibitors derived from dimethylisoxazole skeleton and SAHA.

The representative compound 38 shows potent inhibitory activities against BRD4 and HDAC1 enzymatically and potent anti-proliferative effects against K562 and MV4-11 cells in cellular assays (IC50 values are 1860 and 910 nM respectively). Liu et al [START_REF] Cai | Preparation method of dual HDAC/BRD4 inhibitors for preparation of antitumor agents[END_REF] published a patent about dual BRD4-HDACs inhibitors derived from JQ1 and entinostat. The representative compound 39 not only exhibits potent inhibitory activities against HDAC and BRD4 enzymatically (IC50 values are 31.2 and 29.6 nM, respectively), but also shows greater anti-proliferative effects than its parents JQ1 and entinostat alone. Compound 40 belongs to a series of dual BRD4-HDACs inhibitors derived from RVX-208 and panobinostat [START_REF] Shao | Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors[END_REF]. It shows potent inhibitory activities against BRD4/BD2 and HDAC1 enzymatically and greater anti-proliferative effects against various tumor cells than RVX-208 and panobinostat alone. In 2017, Noguchi-Yachide et al [START_REF] Amemiya | Synthesis and evaluation of novel dual BRD4/HDAC inhibitors[END_REF] reported a series of dual BRD4-HDACs inhibitors based on N 6 -benzoyladenine scaffold [START_REF] Noguchi-Yachide | Discovery and structureactivity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors[END_REF].

Among those analogs reported, compound 41 is a dual BRD4-HDACs inhibitor (IC50 values are 2.7 and 0.26 µM for BRD4 and HDAC respectively). In cellular assays, compound 41 shows moderate anti-proliferative effects against HL-60, K562 and T-47D cells, less potent than SAHA alone. In 2019, Liu et al [START_REF] Cheng | Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents[END_REF] reported a series of novel dual BRD4-HDACs inhibitors derived from P-0014 and SAHA. The representative compound 42 shows moderate inhibitory activities against BRD4 and potent inhibitory activities against HDAC1-3 (good selectivity over HDAC6), but relatively weak anti-proliferative effect against THP-1 cells in cellular assay. Molecular docking experiments reveal that the hydroxamic acid group of compound 42 might form hydrogen bonds with residues from both HDAC and BRD4. In 2020, Sheng et al [START_REF] He | Highly potent dual BET/HDAC inhibitors for the efficient treatment of pancreatic cancer[END_REF]

Dual inhibitors of HDACs-DNA and HDACs-DNMT

Targeting DNA of cancer cells using chemicals such as DNA alkylating agents results in DNA damage and the death of cancer cells. Such a strategy constitutes one of the earliest cancer treatment modalities. However, the DNA damage caused by genotoxic drugs such as chlormethine and bendamustine can be mitigated by cellular DNA repair machinery, which enables some cancer cells to evade and survive. Co-targeting an additional protein/pathway such as HDACs could prove to be a potential solution to the above issue. CY190602 is the first example targeting DNA and HDACs simultaneously [START_REF] Jiang | A mammalian functional-genetic approach to characterizing cancer therapeutics[END_REF]. It is approximately 20~100 fold more cytotoxic against human multiple myeloma cells compared to its parent bendamustine (a single acting agent targeting DNA alone). The synergistic effects provide the foundation for dual HDACs-DNA inhibitors as potential cancer therapy. Compounds 45-47 [START_REF] Liu | A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency[END_REF][START_REF] Xie | Rational design and characterization of a DNA/HDAC dualtargeting inhibitor containing nitrogen mustard and 2-aminobenzamide moieties[END_REF][START_REF] Xie | Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity[END_REF] Azacitidine and decitabine are two DNMTi approved by the US FDA for treatment of hematologic malignancies. Several investigational drugs are currently in various stages of clinical trials [START_REF] Wong | Oncogenic roles and inhibitors of DNMT1, DNMT3A, and DNMT3B in acute myeloid leukaemia[END_REF]. To overcome the limitation of DNMTi in treating solid tumors, the combination of a DNMTi with other anticancer agents or the development of dual targeting agents is urgently needed. As early as 2010, Borden et al [START_REF] Luszczek | Combinations of DNA methyltransferase and histone deacetylase inhibitors induce DNA damage in small cell lung cancer cells: correlation of resistance with IFN-stimulated gene expression[END_REF] discovered that the combination of decitabine and LHB589 synergistically reduced the proliferation of five small cell lung cancer (SCLC) cell lines. In 2017, Baylin et al [START_REF] Topper | Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer[END_REF] reported that the combination of a DNMTi and an HDACi induced a potent antitumor response in NSCLC xenograft mice, and these results became the scientific support for clinical studies. Russo et al [START_REF] Su | Epigenetic reprogramming of epithelial mesenchymal transition in triple negative breast cancer cells with DNA methyltransferase and histone deacetylase inhibitors[END_REF] reported that the combination of SGI-110 (a DNMTi) and entinostat exerted greater antitumor effects both in vitro and in vivo, and such combination might lead to potential treatment for triple-negative breast cancer (TNBC), a type of breast cancers with greater aggressiveness and higher metastasis. Lübbert et al [START_REF] Blagitko-Dorfs | Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation[END_REF] also reported that the combination of decitabine (a DNMTi) and panobinostat produced synergistic anti-proliferative effects against U937 cells. The scientific evidence above prompted the discoveries of several series of dual DNMTs and HDACs targeting agents. Compound 48 (Table 10) [START_REF] Yuan | Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors[END_REF] moderately inhibits DNMT1 and DNMT3B, but potently inhibits HDAC1/6 enzymatically. In cellular assays, compound 48 shows greater anti-proliferative effects against K562 and U937 cells than its parent NSC319745. Similarly, compound 49 shows inhibitory activities against both DNMT1 and HDAC1/6, and strong anti-proliferative effects against histiocytic lymphoma U937 cells (IC50 = 1.3 µM) [START_REF] Ren | Combined inhibition of HDAC and DNMT1 induces p85α/MEK-mediated cell cycle arrest by dual target inhibitor 208 in U937 cells[END_REF]. Compound 50 exhibits moderate inhibitory activities against both DNMTs and HDAC1, and greater anti-proliferative effects against MCF-7, A549, and MDA-MB-231 cells compared to SAHA and SGI-1027 alone [START_REF] Yuan | Development of a versatile DNMT and HDAC inhibitor C02S modulating multiple cancer hallmarks for breast cancer therapy[END_REF].

<insert Table 10>

Dual inhibitors of HDACs and G9a

Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase catalyzing the mono-and di-methylated states of histone H3 at lysine residue 9 (i.e., H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and HeK27me2).

G9a is overexpressed in various cancers including leukemia, HCC, and pulmonary carcinoma [START_REF] Charles | Insights for the design of protein lysine methyltransferase G9a inhibitors[END_REF][START_REF] Cao | Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents[END_REF]. Thus targeting G9a might be potential strategy for cancer therapy, which requires further clinical validation. Since both G9a and HDACs belong to epigenetic modulators, development of dual G9a-HDACs inhibitors might produce synergistic and beneficial effects in cancer therapy. Wang and co-workers [START_REF] Kondengaden | Design and synthesis of small hybrid molecules targeting G9a and HDAC as anticancer agents[END_REF][START_REF] Zang | Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors[END_REF][START_REF] Wang | Histone deacetylase and histone methyltransferase inhibitors and methods of making and use of the same[END_REF] reported a series of dual G9a-HDACs inhibitors based on quinazolin scaffold. The representative compound 51 (Table 11) exhibits moderate inhibitory activities against G9a and HDAC in enzymatic assays, and moderate anti-proliferative effects against MDA-MB-231, MCF-7, A549, and HEK293 cells in cellular assays. <insert Table 11>

Dual inhibitors of HDACs and LSD1

Lysine-specific demethylase 1 (LSD1), also known as KDM1, is the first identified protein lysine demethylases. Through a FAD-dependent oxidative reaction, LSD1 specifically removes histone H3K4me2 to H3K4me1 or H3K4me0. LSD1 is highly expressed in both hematological and solid tumors [START_REF] Hosseini | A comprehensive review of lysine-specific demethylase 1 and its roles in cancer[END_REF]. Thus, drug discovery targeting LSD1 for cancer therapy has been intense both in molecular biology and preclinical stages. Despite several compounds are currently being investigated in clinical trials, there is no approved drug targeting LSD1. Since both LSD1 and HDACs belong to epigenetic modulators, design a small molecule targeting both enzymes might produce synergistic and beneficial effects in cancer therapy. The dual targeting agent compound 52 (Table 12) shows not only stronger LSD1 inhibitory activity than its parent 2-PCPA (IC50 1.2 vs 29.3 µM), but also better selectivity against MAO-A and MAO-B [START_REF] Duan | Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment[END_REF].

When tested head-to-head with SAHA, compound 52 shows comparable inhibitory activities against HDAC1/2, but greater anti-proliferative effects against several cancer cells. Recently Cole and co-workers [START_REF] Kalin | Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors[END_REF] reported a series of dual inhibitors targeting LSD1 and HDACs components of CoREST complex. The representative compound 53 potently inhibits LSD1 and HDACs enzymatically, and produces anti-proliferative effects against cancer cells in cellular assays. Particularly, compound 53 shows excellent anti-proliferative effects against IC1 and MET1 cells, in a level significantly more potent than its parent entinostat alone, or the combination of entinostat and a LSD1 inhibitor. In the in vivo studies in human melanoma SK-MEL-5 cells xenograft mice, administration of compound 53 at 30 mg/kg dose (ip qd) for 28 days led to significant tumor volume inhibition (TVI: 61%) without toxicity signs. In contract, when entinostat was administrated to animals at the same dose and schedule for just one week, 60% of animals died indicating intolerable toxicity. Domatinostat (4SC-202) was originally synthesized as an HDACs inhibitor [START_REF] Maier | N-sulphonylpyrroles and their use as histone deacetylase inhibitors[END_REF], and is currently in several clinical trials. Golas and co-workers reported that the incubation of domatinostat with CRC (C-terminal REST/NRSF-CoREST-LSD1-HDAC1 transcriptional repressor complex) resulted in a significant decrease of the demethylation activity. These results suggest that domatinostat is a dual LSD1-HDACs inhibitor [START_REF] Inui | Stepwise assembly of functional C-terminal REST/NRSF transcriptional repressor complexes as a drug target[END_REF]. However, Cole and co-workers did not observe obvious LSD1 inhibition with domatinostat in their experiment [START_REF] Kalin | Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors[END_REF]. To the best of our knowledge, it is questionable whether domatinostat is a dual LSD1-HDACs inhibitor or just an HDACs inhibitor.

<insert Table 12>

Dual inhibitors of HDACs and EZH2

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase, an enzyme capable of catalyzing the addition of methyl groups to histone H3 at lysine 27 position (H3K27).

EZH2 is overexpressed in a wide range of cancers including breast, prostate, bladder, uterine, renal cancers, melanoma, and lymphoma than in healthy cells. Thus, targeting EZH2 for cancer therapy appears to be an attractive strategy for pharmaceutical industries and academic institutes [START_REF] Kim | Targeting EZH2 in cancer[END_REF]. In March 2020, the first-in-class EZH2 inhibitor tazemetostat (EPZ-6438) was approved by the US FDA for the treatment of adults and adolescents aged ≥ 16 years with locally advanced or metastatic epithelioid sarcoma not eligible for complete resection [START_REF] Hoy | Tazemetostat: first approval[END_REF]. Huntsman et al [START_REF] Wang | Histone deacetylase inhibitors synergizes with catalytic inhibitors of EZH2 to exhibit anti-tumor activity in small cell carcinoma of the ovary, hypercalcemic type[END_REF] reported that the combination of tazemetostat and quisinostat (a pan-HDACs inhibitor experimental drug) led to rapid induction of apoptosis and growth suppression of SCCOHT (small cell carcinoma of the ovary hypercalcemic type, a rare but extremely lethal malignancy ovarian cancer) cells. Synergistic effects against lymphomas using the combination of EZH2 inhibitor GSK126 and HDACi romidepsin were reported by Amengual and co-worker [START_REF] Lue | Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas[END_REF] in both cellular assays and in vivo study. Recently Valente et al [START_REF] Romanelli | Design of first-in-class dual EZH2/HDAC inhibitor: biochemical activity and biological evaluation in cancer cells[END_REF] reported the first-in-class dual EZH2-HDACs inhibitor. The representative compound 55 (Table 13) is an HDAC6selective EZH2-HDACs dual inhibitor. In cellular assays, compound 55 exhibits moderate antiproliferative effects against cells of various cancer types including leukemia, rhabdomyosarcoma, and glioblastoma. However, there is no experimental data in the article to support the synergistic effects of compound 55 vs the combination of two individual drugs.

<insert Table 13>

Dual inhibitors of HDACs and other enzymes

Dual inhibitors of HDACs and IDO

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme physiologically overexpressed in a wide variety of human tumors. IDO1 catalyzes the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine.

Increased IDO1 expression is associated with a poor prognosis in cancer patients. Several IDO1 inhibitors such as linrodostat (BMS-986205) and epacadostat (INCB024360) are currently in various stages of clinical investigation in the combination with other therapies [START_REF] Yentz | Indoleamine 2,3-dioxygenase (IDO) inhibition as a strategy to augment cancer immunotherapy[END_REF]. The monotherapy using an IDO inhibitor is known to have limited antitumor effects in both preclinical and clinical studies. To explore the potential of IDO1 inhibition, Sheng and co-workers [START_REF] Fang | Discovery of novel indoleamine 2,3-dioxygenase 1 (IDO1) and histone deacetylase (HDAC) dual inhibitors[END_REF] designed and synthesized the first generation of dual IDO-HDACs inhibitors from epacadostat and mocetinostat (a pan-HDAC inhibitor experimental drug). The representative compound 56 (Table 14) is a dual IDO1-HDACs inhibitor (IDO1 and HDAC1 IC50 values are 69 and 66.5 nM respectively) with no selectivity across HDACs subtypes. Compound 56 is orally bioavailable (F% = 18%) indicated by the pharmacokinetic studies in SD rats at 100 mg/kg oral dose and 2 mg/kg iv dose. Administration of compound 56 at 100 mg/kg bid dosing for 14 days in LLC mouse model resulted in -56% of tumor growth inhibition. Other dual inhibitors 57 and 58 are less characterized in term of in vitro activities and pharmacology [START_REF] Zhang | Polycyclic compound acting as IDO inhibitor and/or IDO-HDAC dual inhibitors[END_REF][START_REF] Zhang | Preparation method for six-membered cyclic formamide compound used as IDO/HDAC dual-target inhibitor for the treatment of malignant tumor[END_REF].

<insert Table 14>

Dual inhibitors of HDACs and Topoisomerases

DNA topoisomerases (Topoisomerases, or Topos) are enzymes that modulate DNA topology such as overwinding or underwinding. These enzymes play essential roles in controlling topological DNA problems during cell proliferation, differentiation, and survival.

Several drugs targeting Topos have been approved for cancer therapy [START_REF] Liang | A comprehensive review of topoisomerase inhibitors as anticancer agents in the past decade[END_REF][START_REF] Delgado | Topoisomerases as anticancer targets[END_REF]. However, drugs targeting Topos have limitations, such as dose-limiting toxicity, drug resistance, and development of secondary malignancies. Searching for dual inhibitors against Topos and an additional target could potentially overcome the above limitations. Dual Topos-HDACs inhibitors published prior to 2015 have been reviewed [START_REF] Seo | Dual Inhibitors Against Topoisomerases and Histone Deacetylases[END_REF], and the dual inhibitors published after 2015 will be covered in this article. Dallavalle et al reported two series of dual Topos-HDACs inhibitors based on camptothecin (CPT, a known Topos inhibitor natural product currently in various stages of clinical trials) scaffold, but with the different side chain of HDAC pharmacophore. Compound 59 (Table 15) [START_REF] Cincinelli | Camptothecin-psammaplin a hybrids as topoisomerase I and HDAC dual-action inhibitors[END_REF] is the representative compound from the first series bearing a unique HDAC pharmacophore of psammaplin A, while compound 60 [START_REF] Cincinelli | Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents[END_REF] is from the second series bearing SAHA pharmacophore. Both compounds 59 and 60 are potent dual Topos-HDACs inhibitors, with excellent inhibitory activities against HDACs and potent anti-proliferative effects against a wide range of cancer cells. In in vivo studies, compound 59

shows strong antitumor effects in human mesothelioma primary cell line MM487 xenograft CD-1 nude mice with a very high safety profile. On the other hand, compound 60 shows excellent antitumor effects in MM473 xenograft CD-1 nude mice after 8 days treatment. Compound 61 [START_REF] Chen | Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors[END_REF] was derived from amsacrine (a Topo II inhibitor medicine) and SAHA. It shows excellent inhibitory activities against HDACs and potent anti-proliferative effects against various cancer cells. Derived from a known Topos inhibitor [START_REF] Matsumoto | Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides[END_REF], compound 62 [START_REF] Yamashita | Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors[END_REF] shows good inhibitory activities against HDACs in enzymatic assays, and good anti-proliferative effects against several cancer cells in cellular testing. Compound 63 [START_REF] Joshi | Epharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylase[END_REF] derived from pyrozoloquinazoline scaffold and SAHA, shows moderate inhibitory activity against Topo I and good inhibitory activity against HDAC1. In cellular assays, compound 63 exhibits strong anti-proliferative effects against several cancer cells.

<insert Table 15>

Dual inhibitors of HDACs and PARP

Poly (ADP-ribose) polymerase (PARP) family is a 17-membered family of enzymes comprising a DNA-binding domain, a catalytic domain, and an auto-modification domain. These enzymes participate in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death. PARP inhibitors' ability in causing cancer cells death through "synthetic lethality" mechanism has been validated in the clinic, resulting in several approved drugs in this field for cancer therapy [START_REF] Ashworth | Synthetic lethal therapies for cancer: what's next after PARP inhibitors?[END_REF][START_REF] Yi | Advances and perspectives of PARP inhibitors[END_REF][START_REF] Mateo | A decade of clinical development of PARP inhibitors in perspective[END_REF]. Olaparib (2014), rucaparib (2016), niraparib (2017), and talazoparib (2018) are four drugs approved by the US FDA for treatment of ovarian cancer of all settings and breast cancer with BRCA1/2 mutation. Despite the success of PARPi as a monotherapy, two major limitations remain: efficacy largely restricted to BRCA1/2-mutated tumors and the resistance developed over time [START_REF] Noordermeer | PARP inhibitor resistance: a tug-of-war in BRCAmutated cells[END_REF][START_REF] D´andrea | Mechanisms of PARP inhibitor sensitivity and resistance[END_REF]. Besides the combination strategy currently being assessed in preclinical and clinical stages [START_REF] Dréan | PARP inhibitor combination therapy[END_REF], development of a single molecule inhibiting PARP and other cancer-relevant targets might potentially overcome the above limitations. The synergistic effects of combining a PARPi and HDACi have been well documented in the literature [START_REF] Chao | Synergistic loss of prostate cancer cell viability by coinhibition of HDAC and PARP[END_REF][START_REF] Ha | Histone deacetylase inhibitor treatment induces BRCAness and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells[END_REF][START_REF] Rasmussen | Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma[END_REF][START_REF] Marijon | Cotargeting poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) in triplenegative breast cancer: higher synergism in BRCA mutated cells[END_REF]. Those results lay foundation for development of dual PARP-HDACs inhibitors. There are two series of dual PARP-HDACs inhibitors reported to date, both derived from olaparib scaffold. Compound 64 (Table 16) [START_REF] Yuan | Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy[END_REF] incorporates part of the linker and hydroxamic acid from panobinostat into olaparib, while compound 65 [START_REF] Tian | Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors[END_REF] adopts the HDAC pharmacophore from chidamide. Both compounds show potent inhibitory activities against PARP and HDACs in enzymatic assays, and moderate anti-proliferative effects against various cancer cells in cellular assays.

<insert Table 16>

Dual inhibitors of HDACs and NAMPT

Nicotinamide phosphoribosyltransferase (NAMPT), a member of glycosyltransferases family, is a rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD + ) salvage pathway that converts nicotinamide to nicotinamide mononucleotide in mammals to enable NAD + biosynthesis. As various tumor cells exhibit an increased reliance on NAD + production pathways, targeting NAMPT might be a potential cancer therapy. Despite promising preclinical results in animal models, several NAMPT inhibitors showed limited anticancer efficacy in early phase clinical trials [START_REF] Heske | Beyond energy metabolism: exploiting the additional roles of NAMPT for cancer therapy[END_REF]. Dual NAMPT-HDACs inhibitors might potentially enhance the efficacy compared to NAMPT inhibitors alone. Through pharmacophore analysis and molecular docking experiment, Sheng et al [START_REF] Wu | Nicotinamide phosphoribosyltransferase (NAMPT) is a new target of antitumor agent chidamide[END_REF] inferred that the known HDACi drug compound 66 (chidamide) (Table 17) could potentially inhibit NAMPT as well. They then confirmed chidamide's inhibitory activity against NAMPT via biological assay (IC50: 2.1 µM). Compound 66 appears to be the first known dual NAMPT-HDACs inhibitor. The characterization of compound 66 in various cancer cells was documented in literature.

<insert Table 17>

Dual inhibitors of HDACs and MMPs

Matrix metallopeptidases (MMPs) are calcium-dependent zinc-containing endopeptidases not only capable of degrading all kinds of extracellular matrix proteins, but also having ability to process a number of bioactive molecules. Besides cleaving cell surface receptors, releasing apoptotic ligands, and inactivating chemokine/cytokine, MMPs also play a major role in cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense. For at least half century, MMPs have been heralded as promising targets for cancer therapy based on their molecular biology and their compelling preclinical study results [START_REF] Coussens | Matrix metalloproteinase inhibitors and cancer: trials and tribulations[END_REF][START_REF] Laronha | Challenges in matrix metalloproteinases inhibition[END_REF]. Unfortunately, the clinical results are disappointing. Cotargeting an additional cell signaling pathway or enzyme or protein could potentially enhance the efficacy of MMPs inhibitors. Dual MMPs-HDACs inhibitors reported prior to 2015 have been reviewed by Jha et al [START_REF] Amin | Is dual inhibition of metalloenzymes HDAC-8 and MMP-2 a potential pharmacological target to combat hematological malignancies?[END_REF]. Compound 67 (Table 18) [START_REF] Halder | Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity[END_REF] shows moderate inhibitory activities against MMP-2, MMP-9, and HDAC8 with good selectivity over other NMPs and HDACs subtypes. Zhang et al [START_REF] Wang | Hierarchical virtual screening of the dual MMP-2/HDAC-6 inhibitors from natural products based on pharmacophore models and molecular docking[END_REF] utilized virtual screening to identify four natural products, which are potential dual MMP-2-HDAC6 inhibitors. However, no further follow-up work has been reported. <insert Table 18>

Dual inhibitors of HDACs and nuclear receptors 2.4.1 Dual inhibitors of HDACs and androgen receptor (AR)

Androgen receptor (AR) is a type of nuclear receptor activated by androgenic hormones, including testosterone and dihydrotestosterone (DHT) in the cytoplasm and then translocating into the nucleus. AR increases the cell survival and proliferation by DNA dependent and independent mechanism. Due to its important role in male reproductive systems and homeostasis of bone and muscle, targeting AR through antagonist, agonist, or selective modulator has been validated as potential treatment for cancers, especially for prostate cancer [START_REF] Fujii | Androgen receptor modulators: a review of recent patents and reports (2012-2018[END_REF]. Apalutamide (ARN-509) is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. Derived from SAHA pharmacophore and apalutamide, compound 68 (Table 19) is a dual AR-HDACs inhibitor. In the anti-proliferation assay against LNCaP cells, compound 68 shows greater activity than apalutamide (ARN-509) [START_REF] Meng | Preparation of hydantoin compounds with dual inhibitory effects of androgen receptor (AR) and histone deacetylase (HDAC) for treating prostatic cancer[END_REF]. The dual AR-HDACs inhibitor might have potential treatment benefit for anti-cachectic therapy [210] or castration-resistant prostate cancer [START_REF] Feng | Androgen receptor signaling in the development of castration-resistant prostate cancer[END_REF]. <insert Table 19>

Dual estrogen receptor (ER)-HDACs targeting agent

Estrogen receptors (ERs) are a group of proteins found inside cells that are activated by the hormone estrogen (17β-estradiol). Abnormal ERs signaling leads to the development of a variety of diseases, especially breast cancer [START_REF] Jia | Estrogen receptor alpha and beta in health and disease[END_REF]. The approval drug ERs antagonist tamoxifen can be used for treatment of half of ERs + breast cancer, but not ERs -or triple-negative breast cancer (TNBC). In addition, another half of ER + breast cancer cases often develop the resistance to tamoxifen due to a down-regulation of ERα corepressors. The link between ERα corepressors and HDACs in tamoxifen-resistance breast cancer reveals that an HDACi could effectively reverse tamoxifen resistance, and could be a potential therapy for this specific type of breast cancers [START_REF] Basik | Minireview: the link between ER corepressors and histone deacetylases in tamoxifen resistance in breast cancer[END_REF]. Derived from known ER antagonist [START_REF] Zhou | Synthesis and evaluation of estrogen receptor ligands with bridged oxabicyclic cores containing a diarylethylene motif: estrogen antagonists of unusual structure[END_REF], compound 69 (Table 20) was reported as a dual ERs-HDACs targeting agent with potent inhibitory activity against ERα, ERβ, and HDAC1 [START_REF] Tang | Novel bioactive hybrid compounds dual targeting estrogen receptor and histone deacetylase for treatment of breast cancer[END_REF]. In cellular assays, compound 69 shows greater potency than its parent OBHS against both breast cancer MCF-7 cells and prostate cancer DU-145 cells.

<insert Table 20> 2.5 Miscellaneous

Dual inhibitors of HDACs and HSP90

HSP90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. The ability of HSP90 to stabilize a number of proteins required for tumor growth makes it an attractive drug target for potential anti-cancer therapy. Several papers reported that the combination of HDACi and HSP90 inhibitor could produce synergistic anti-cancer effects. These results provide the foundation for rational design of dual inhibitors targeting HDACs and HSP90 simultaneously [START_REF] Kim | Novel heat shock protein 90 inhibitor NVP-AUY922 synergizes with the histone deacetylase inhibitor PXD101 in induction of death of anaplastic thyroid carcinoma cells[END_REF][START_REF] Kim | The heat shock protein 90 inhibitor SNX5422 has a synergistic activity with histone deacetylase inhibitors in induction of death of anaplastic thyroid carcinoma cells[END_REF][START_REF] Rahmani | Coadministration of the heat shock protein 90 antagonist 17-allylamino-17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells[END_REF][START_REF] George | Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3[END_REF][START_REF] Krämer | Drugging the HDAC6 HSP90 interplay in malignant cells[END_REF]. Derived from a known HSP90 inhibitor and SAHA, compound 70 (Table 21) [START_REF] Mehndiratta | N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PDL-1 expression[END_REF] is a potent HSP90α-HDAC6 dual inhibitor. When tested in several cancer cells, compound 70 shows anti-proliferative effects at 1 µM concentration, better than SAHA alone. Importantly, compound 70 can reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated H1975 lung cancer cells in a dose dependent manner. The result suggests that dual HDACs-HSP90 inhibitors have capability to modulate immunosuppression of tumor microenvironment, and might provide direction for future cancer treatment. Recently Rastelli et al [START_REF] Luca | Design of dual inhibitors of histone deacetylase 6 and heat shock protein 90[END_REF] predicted compound 71 as a dual HSP90-HDAC6 inhibitor using an integrated ligand-based and structurebased virtual screening approach. The prediction was further verified through chemical synthesis and biological testing, and compound 71 was reported to have moderate inhibitory activity against both HDAC6 and HSP90. <insert Table 21>

Dual inhibitors of HDACs and Tubulin

Microtubules, a major component of the eukaryotic cytoskeleton, are formed from the polymerization of α-and β-tubulins and function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division [START_REF] Brouhard | Microtubule dynamics: an interplay of biochemistry and mechanics[END_REF]. There are two classes of tubulin-targeting drugs: depolymerization inhibitors such as paclitaxel and epothilone and polymerization inhibitors such as colchicine and combretastatins. The synergistic effects of combining an anti-tubulin agent with an HDACi have been well documented in the literature [START_REF] Dowdy | Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells[END_REF][START_REF] Zuco | Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo[END_REF][START_REF] Konishi | Acetylation of αtubulin by a histone deacetylase inhibitor, resminostat, leads synergistic antitumor effect with docetaxel in non-small cell lung cancer models[END_REF]. A couple of papers disclosed dual tubulin-HDACs inhibitors prior to 2015. This paper will focus on those dual inhibitors published since 2015. Derived from colchicine and entinostat, compound 72 (Table 22) [START_REF] Zhang | Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors[END_REF] shows powerful tubulin inhibitory activity and moderate HDACs inhibitory activity, and also exhibits superior cytotoxicity comparing to the positive control (IC50 2 to 105 nM). Compound 73 [START_REF] Lamaa | Design and synthesis of tubulin and histone deacetylase inhibitor based on iso-combretastatin A-4[END_REF] shows potent inhibitory activities against tubulin polymerization and HDAC8, and impressive anti-proliferative effects against various cancer cells. Its close analog 74 [START_REF] Wang | Anti-tumor activity evaluation of novel tubulin and HDAC dual-targeting inhibitors[END_REF] appears to be HDAC6-selective dual inhibitor with weaker antitubulin polymerization activity (IC50 54.5 µM). In cellular assays, compound 74 shows potent anti-proliferative effects against several cancer cells including A549, HeLa, and SGC-7901.

Compound 75 [START_REF] Wang | SKLB-23bb, a HDAC6selective inhibitor, exhibits superior and broad-spectrum antitumor activity via additionally targeting microtubules[END_REF][START_REF] Yang | Discovery of selective histone deacetylase 6 inhibitors using the quinazoline as the cap for the treatment of cancer[END_REF] is also an HDAC6-selective dual tubulin-HDACs targeting agent. In addition to HDACs inhibitory activities, it induces acetylation of α-tubulin and inhibits tubulin polymerization. In cellular assays, compound 75 exhibits greater anti-proliferation potency against a variety of cancer cells than ricolinostat (a pan-HDAC inhibitor). Compound 76 [START_REF] Luan | Histone deacetylase and tubulin dual target inhibitors and preparation method thereof and application thereof in preparing tumor drugs[END_REF],

an analog by incorporating a thiol ester ZBG into the same scaffold, is a dual tubulin-HDACs targeting agent as compound 75, but with weaker biological activities comparing to 75.

BPR0L075 [START_REF] Kuo | BPR0L075, a novel synthetic indole compound with antimitotic activity in human cancer cells, exerts effective antitumoral activity in vivo[END_REF], an indole analog bearing colchicine binding site, shows antimitotic activity against several cancer cells. Compound 77 [START_REF] Lee | 3-Aroylindoles display antitumor activity in vitro and in vivo: effects of N1-substituents on biological activity[END_REF][START_REF] Wu | A novel dual HDAC6 and tubulin inhibitor, MPT0B451, displays anti-tumor ability in human cancer cells in vitro and in vivo[END_REF] was derived from installing belinostat's side chain to the indole nitrogen of BPR0L075. Cell cycle analysis indicated that mitotic arrest was induced by compound 77 with enhanced expression of G2/M transition proteins. Molecular docking experiment supports compound 77 as a dual tubulin-HDAC6 inhibitor. Furthermore, compound 77 exhibits tumor growth inhibition in HL-60 and PC-3 xenograft mice upon administrating compound to animals via both oral and ip dosing.

<insert Table 22>

Dual inhibitors of HDACs and MDM2

Mouse double minute 2 homolog, also known as E3 ubiquitin-protein ligase MDM2, is an important negative regulator of the p53 tumor suppressor gene. It functions as both an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and an inhibitor of p53 transcriptional activation. Blocking the p53-MDM2 proteinprotein interaction with small-molecule inhibitors can reactivate the function of p53 and is emerging as a promising strategy in cancer therapy [START_REF] Liu | The past, present and future of potential small-molecule drugs targeting p53-MDM2/MDMX for cancer therapy[END_REF][START_REF] Burgess | Clinical overview of MDM2/X-targeted therapies[END_REF]. Sheng et al [START_REF] He | Small molecules simultaneously inhibiting p53-murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs): discovery of novel multitargeting antitumor agents[END_REF] reported a series of dual MDM2-HDACs inhibitors derived from nutlin-3 and SAHA. The representative compound 78 (Table 23) not only potently inhibits MDM2 and HDACs enzymatically but also exhibits strong anti-proliferation effects against several cancer cells in cellular level.

Pharmacokinetic studies indicate that compound 78 is orally bioavailable in SD rats (%F = 18%).

In A549 xenograft mice, compound 78 effectively inhibits tumor growth with no significant weight loss and no adverse effects. In a Chinese patent filed in 2018 [START_REF] Xu | MDM2-HDAC dual target inhibitor, pharmaceutical composition, its preparation and application[END_REF], several series of dual MDM2-HDACs inhibitors based on multi-substituted or polycyclic pyrrolidine cores were claimed. The representative compound 79 shows potent inhibitory activity against both MDM2 and HDACs. No further characterization is available. <insert Table 23>

Dual inhibitors of HDACs and CRBN

Cereblon (CRBN) functions as a substrate receptor for the CRL4 ubiquitin ligase complex to target protein, and promotes ubiquitination and proteasomal degradation of CRBN substrates, such as IKZF1 and IKZF3. Immunomodulatory drugs (IMiD) such as lenalidomide are used to treat hematologic malignances primarily through targeting CRBN [START_REF] Asatsuma-Okumura | Molecular mechanisms of cereblon-based drugs[END_REF]. Tang et al [START_REF] Tang | Synthesis of small molecule histone deacetylase 6 degraders, compounds formed thereby, and pharmaceutical compositions containing them[END_REF][START_REF] Wu | Development of multifunctional histone deacetylase 6 degraders with potent antimyeloma activity[END_REF] designed a series dual CRBN-HDACs targeting agents by incorporating HDACs pharmacophore to pomalidomide scaffold via a triazole linker. The representative compound 80 (Table 24) not only potently inhibits HDAC6 (IC50 ≤ 10 nM) but also exhibits a promising degradation activity (DC50 = 1.6 nM) against IKZF (Ikaros family zinc finger protein), 3 to 5fold improved than the previous reported dual targeting agent [START_REF] Yang | Development of the first small molecule histone deacetylase 6 (HDAC6) degraders[END_REF]. Compound 80 exhibits greater anti-proliferative effects against MM1S multiple myeloma cells than the combination of pomalidomide and nexturastat A at an 1 to 1 ratio, and the result further testifies the advantage of dual acting agents over single acting agents alone or their combination. <insert Table 24>

Dual inhibitors of HDACs and proteasomes

Proteasomes are protein complexes capable of performing proteolysis (a chemical reaction that breaks peptide bonds) to selectively degrade unneeded or damaged proteins labelled with ubtiquitins. Proteasomes play a crucial role in the fate of proteins that are involved in almost all of the major cellular processes. Small molecules targeting proteasomes through inhibition can induce apoptosis in tumor cells, and have been validated as effective cancer therapy in animal models and clinical trials. Three approval drugs for treatment of multiple myeloma are bortezomib, carfilzomib, and ixazomib. The synergistic effects of the combination of a proteasome inhibitor with an HDACi for the treatment of multiple myeloma were well documented [START_REF] Hideshima | Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma[END_REF], and might provide scientific rationale for design dual proteasome-HDAC inhibitors. Compound 81 [START_REF] Bhatia | Discovery of the first-in-class dual histone deacetylase-proteasome inhibitor[END_REF] is a dual proteasome-HDACs inhibitor supported by biochemical and cellular assays (Table 25). The X-ray co-crystal structures of the 20S proteasome complexed with 81 and HDAC6 complexed with 81 were solved to further verify its dual acting functions.

<insert Table 25>

Dual agents targeting HDACs and NO-donor

Nitric oxide (NO) is a well-known gaseous molecule that plays important roles in mammalian physiology and pathophysiology. Besides its roles in the cardiovascular system for vascular homeostasis [START_REF] Jin | Vascular nitric oxide: formation and function[END_REF], in the central nervous system for learning and memory formation [START_REF] Esplugues | NO as a signalling molecule in the nervous system[END_REF], and in skeletal muscles for modulating contraction excitation coupling [START_REF] Stamler | Physiology of nitric oxide in skeletal muscle[END_REF], nitric oxide also exhibits interesting inhibitory activity against tumor cells proliferation [START_REF] Nathan | Role of nitric oxide synthesis in macrophage antimicrobial activity[END_REF], angiogenesis, and metastasis [START_REF] Stuehr | Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells[END_REF]. Hence, nitric oxide could potentially accelerate tumor cell apoptosis [START_REF] Bonfoco | Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-Daspartate or nitric oxide/superoxide in cortical cell cultures[END_REF] and retard the development of drug resistance [START_REF] Konovalova | Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance[END_REF]. The inducible nitric oxide synthase (iNOS) is an enzyme capable of producing a heavy dose of cellular NO biologically, while a chemical NO donor (or a small molecule bearing the such) is identified or devised by scientists to release cellular NO chemically. Among those chemical NO donors are oxadiazole [START_REF] Maksimovic-Ivanic | Anticancer properties of the novel nitric oxide-donating compound (S,R)-3phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo[END_REF], sodium nitroprusside (SNP) [START_REF] Wang | Nitric oxide donors: chemical activities and biological applications[END_REF], and oleanolic acid derivatives [START_REF] Chen | Design, synthesis, and antihepatocellular carcinoma activity of nitric oxide releasing derivatives of oleanolic acid[END_REF], all exhibit interesting cytotoxicity and antitumor activity against various tumor cells. Fruttero et al [START_REF] Borretto | Synthesis and biological evaluation of the first example of NO-donor histone deacetylase inhibitor[END_REF] reported the first example of dual NO donor-HDACs targeting agent 82 (Table 26) by attaching a NO releasing group onto entinostat. In molecular biology studies, compound 82 affects a number of micro-RNAs not modulated by entinostat or NO-releasing group alone, indicating the synergy effects produced from both HDAC inhibition and NO release. Derived from phenylsulfonylfuroxan and SAHA, compound 83 [START_REF] Duan | Design, synthesis and antitumor evaluation of novel histone deacetylase (HDAC) inhibitors equipped with phenylsulfonylfuroxan module as nitric oxide (NO) donor[END_REF] displays strong NO-releasing ability and potent inhibitory activities against HDACs. Mechanistic studies reveal that 83 can induce a much stronger apoptotic effect and G1 phase arrest in HEL cells than SAHA, a result contributed by both HDACs inhibition and NO release. Compound 84 [START_REF] Atlante | Structural and biological characterization of new hybrid drugs joining an HDAC inhibitor to different NO-donors[END_REF], a close analog of 82 but with different NO-releasing group, might be severed as a therapeutic tool molecule for cardiovascular, neuromuscular, and inflammatory diseases as it possesses muscle differentiation function. The thio ester prodrug 85 [START_REF] Borgini | Synthesis and antiproliferative activity of nitric oxide-donor largazole prodrugs[END_REF] is found to release largazole (an HDACs inhibitor) and NO upon ester hydrolysis. In cellular assay, 85 shows greater anti-proliferative effects against U-2OS and IMR-32 cells than largazole alone, indicating additive effects contributed from NO release.

<insert Table 26>

Clinical trials of dual targeting agents containing HDACs component

Dual targeting agents containing HDACs component have been an emerging area in cancer therapy, with the number of publications increasing significantly and several candidates advancing to various stages of clinical trials. Among all the dual acting agents, Curis, Inc.'s fimepinostat (CUDC-907) (Table 27) is the most advanced one, targeting PI3K and HDACs simultaneously. In 2013, fimepinostat entered into Phase I trial to determine the maximal tolerated dose, the recommended Phase II dose (RP2D), and the preliminary anti-cancer activity as monotherapy in patients with relapsed or refractory lymphomas or multiple myeloma. Within 25 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) enrolled in this study, 9 objective responses (3 complete responses and 6 partial responses) were reported in 21-response-evaluable patients. Further analysis of the tumors from 9 patients who achieved objective responses confirmed 5 of them had MYC oncogene alterations. Thereby, MYC oncogene alteration could be an important biomarker for patient stratification in the future clinical trials. The recommended dose of fimepinostat for further Phase 2 development was determined to be once-daily oral administration of 60 mg dose using a 5 days "on" and 2 days "off" schedule, in a 21-day cycle. The most common drug-related adverse events (AEs) reported in the study were low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) consisted of diarrhea and hyperglycemia, however no DLTs occurred at the RP2D. Other drug-related Grade 3 or Grade 4 AEs reported in 3 or more patients included thrombocytopenia and neutrophil decrease (hematologic AEs) as well as diarrhea, hyperglycemia and fatigue (nonhematologic AEs). In 2015, the US FDA granted fimepinostat orphan drug designation for the treatment of patients with DLBCL. In 2018, the US FDA granted Fast Track designation for the development of fimepinostat in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy [260]. Recent results reported by Ge et al [START_REF] Hu | CUDC-907, a novel dual PI3K and HDAC inhibitor, in prostate cancer: Antitumour activity and molecular mechanism of action[END_REF] and Okabe et al [START_REF] Okabe | Effect of dual inhibition of histone deacetylase and phosphatidylinositol-3 kinase in Philadelphia chromosome-positive leukemia cells[END_REF] suggested that fimepinostat would be an effective treatment for ABL TKI-resistant cells (including cells harboring the T315I mutation) as well as resistant prostate cancer cells. CUDC-101 [START_REF] Shimizu | Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors[END_REF][START_REF] Galloway | A phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma[END_REF], an investigational drug also developed by Curis, Inc., is a multitarget inhibitor of HDACs, EGFR, and HER2. There are 4 Phase I clinical trials on the US clinical trial website, 3 of them being listed as completed, and one being listed as terminated.

The termination is likely due to the safety issues. As of today, CUDC-101 is no longer existing as developmental candidate in Curis, Inc. company website. Domatinostat (4SC-202) was originally synthesized as a pan-HDACs inhibitor [START_REF] Maier | N-sulphonylpyrroles and their use as histone deacetylase inhibitors[END_REF], and later was reported to also possess the inhibitory activity against LSD1. In a Phase I study with 24 heavily pretreated patients with several types of advanced hematologic cancers, domatinostat was found to be well tolerated, with positive signs of anti-tumor efficacy observed (one complete remission (28 months) and one partial responder (8 months)). It is currently in four active clinical trials either alone or in combination with a PD-1, PDL-1, or CTLA-4 antibodies. The clinical trials designs with antibodies are supported by preclinical studies that domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment [START_REF] Bretz | Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)[END_REF]. In January 2019, the Germany-based company 4SC AG announced that domatinostat began Phase II gastrointestinal cancer clinical trial.

Tinostamustine is a dual acting agent targeting both DNA and HDACs. It is being developed by Mundipharma EDO GmbH Therapeutics L.P., a subsidiary of Purdue Pharma L.P., for the treatment of hematological malignancies, solid tumors, multiple myeloma, and glioblastoma. The preclinical studies not only demonstrated that tinostamustine could improve access to cancer cells' DNA strands, break them, and suppress damage repair, but also exhibited the potential to overcome resistance toward some other cancer treatments utilizing its complementary and simultaneous actions on both DNA and HDACs. In April 2019, the US FDA has granted orphan drug status to tinostamustine for the treatment of T-cell prolymphocytic leukemia (T-PLL), an aggressive type of leukemia with very limited treatment options.

<insert Table 27>

Future directions

The number of publications describing dual inhibitors containing HDACs component increases significantly in the past 5 years, which indicates that this area of research excites great interests for the scientific community. From the analysis above, one can realize that HDACs inhibitory activity might be obtained in a relatively easy way, through attachment of the HDACs pharmacophore to lead molecules (or drugs) via a suitable linker. The design and construction of such dual acting agents are feasible and manageable using medicinal chemistry tactics so as not to compromise the biological activity of lead molecules (or drugs) on the parent targets. The said biological targets pairing with HDACs could be as broad as one can imagine, namely from kinases to epigenetic targets to receptors to other enzymes and so on, based on the target function category. In many cases, the synergistic anti-tumor effects are clearly established with these dual inhibitors in enzymatic levels, and/or in cellular levels, and in some cases in in vivo animal models as well. Besides those biological targets described in this article, more and more additional ones are being discovered to have synergistic effects with HDACs. For example, Ramakrishnan et al [START_REF] Ramakrishnan | Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma[END_REF] reported that the combination of MEK1/2 inhibitor selumetinib (an investigational drug from AstraZeneca) with panobinostat (a pan-HDACs inhibitor approved drug) demonstrates synergistic apoptosis in Ras/RAF mutated multiple myeloma cell lines. Such results could further spark the discovery of dual MEK-HDACs inhibitors in the near future. It should be noted that this article only intended to include cancer-related targets as dual acting agents. Other non-cancer-related targets such as PDE are reported to have synergistic effects with HDACs as well [START_REF] Han | Discovery of novel fungal lanosterol 14αdemethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors to treat azole-resistant candidiasis[END_REF][START_REF] Rabal | Design, synthesis, and biological evaluation of first-in-class dual acting histone deacetylases (HDACs) and phosphodiesterase 5 (PDE5) inhibitors for the treatment of Alzheimer s disease[END_REF][START_REF] Cuadrado-Tejedor | A first-in-class small-molecule that acts as a dual inhibitor of HDAC and PDE5, and that rescues hippocampal synaptic impairment in Alzheimer's disease mice[END_REF][START_REF] Sánchez-Arias | Impact of scaffold exploration on novel dual-acting histone deacetylases and phosphodiesterase 5 inhibitors for the treatment of Alzheimer's disease[END_REF][START_REF] Rabal | Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease[END_REF][START_REF] Rabal | Discovery of in vivo chemical probes for treating Alzheimer s disease: dual phosphodiesterase 5 (PDE5) and class I histone deacetylase selective inhibitors[END_REF][START_REF] Rabal | Multitarget approach for the treatment of Alzheimer's disease: inhibition of phosphodiesterase 9 (PDE9) and histone deacetylases (HDACs) covering diverse selectivity profiles[END_REF][START_REF] Elhady | Extending the use of tadalafil scaffold: development of novel selective phosphodiesterase 5 inhibitors and histone deacetylase inhibitors[END_REF], but they are out of the scope of this article.

One of the biggest challenges in this field is to improve oral bioavailability of the dual acting agents. Among those described above, several compounds show poor oral bioavailability despite of the good ip bioavailability (i.e. compound 24 oral bioavailability <1%, ip bioavailability >100%). This could be in part due to the nature of HDACs pharmacophore (i.e. hydroxamic acid), which has been documented in literature as labile metabolic functional group.

However, some compounds are reported to have good oral bioavailability and they also bear similar HDACs pharmacophore. For example, the following compounds have good oral bioavailability: compounds 7 (73%), 8 (18%), 25 (18%), 26 (41%), 44 (40.5%), 56 (18%), 75 (47%), and 78 (18%). It's convinced that the oral bioavailability might be governed by many factors including the overall physical chemical properties of the entire molecule, rather than just by the nature of HDACs pharmacophore hydroxamic acid functional group. Such hurdle might be addressed through medicinal chemistry design and iterative optimization.

When designing dual inhibitors targeting HDACs and additional cancer-related target, one might also need to consider the subtype-selectivity for HDACs. Recent advances suggest that selectivity of certain HDAC subtypes such as HDAC6 might produce better safety profiles comparing to pan-HDACs inhibition [START_REF] Wang | Recent advances in the discovery of potent and selective HDAC6 inhibitors[END_REF][START_REF] He | Novel selective histone deacetylase 6 (HDAC6) inhibitors: a patent review (2016-2019)[END_REF].

Either HDACs component or its counterpart, or both might contribute to potential side effects for HDACs-containing dual targeting agents. This should be taken into consideration when designing dual inhibitors. Unfornately, there is no rule or enough knowledge that can help us effectively predict such side effects. Testing these dual targeting agents in an in vivo experiment might be the only solution. Within the literature we discuss above, the body weights of tested animals were assessed as one of criteria for side effects. For example, CDKs-HDACs dual inhibitor 8, JAK-HDACs dual inhibitor 24, BRD-HDAcs dual inhibitors 43 and 44 all showed no significant weight loss at their efficacious doses.

Despite of large number of publications for dual targeting agents, there are only 9 papers describing in vivo pharmacological effects. The rest papers focus only on in vitro activity. Due to the limited data reported, it is difficult to conclude that single agents inhibiting both HDACs and other targets have definitely pharmacological superiority than the combination of the two individual drugs. We anticipate that more data for such direct comparison will appear in publications in the future.

The advantages of dual targeting agents over the combination strategy are being recognized gradually by scientific community, and the dual targeting agents might become the future trend for cancer therapy. Since this approach involves multiple biological targets (HDACs and other), in vivo studies for selected compounds require comprehensive design, for example taking consideration of the in vitro activities of all targets involved. In some cases, exploration through rational experimental studies might be the only solution. The dual PI3K-HDACs inhibitor fimepinostat (CUDC-907) is the most advanced compound in this field, which is currently in various stages of clinical trials. It's hopeful that more and more dual targeting agents will be identified and advanced to clinical stage, and will ultimately lead to approval drugs from this category to combat cancers.

Corresponding Authors

*Xiang-Yang Ye: phone 011-571-28860236, e-mail: xyye@hznu.edu.cn; *Tian Xie: phone: 011-571-28860237, email: xbs@hznu.edu.cn; *Carmen Garrido: phone 00-33-380393256, email: cgarrido@u-bourgogne.fr.

Notes

The authors declare no competing financial interest.

Abbreviations

AML, acute myeloid leukemia; AR, androgen receptor; ATC, anaplastic thyroid cancer; Bcr, break point cluster; AUC, area under curve; BET, bromodomain and extra-terminal; bid, bis in die; CDKs, Cyclin-dependent kinases; CETSA, cellular thermal shift assay; CK2, casein kinase 2; CML, chronic myelogenous leukemia; CNS, central nervous system; CRBN, Cereblon; DLBCL, diffuse large B-cell lymphoma; DMAT, 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole; DNMTs, DNA methyltransferases; EGFR, epidermal growth factor receptor; EHMT2, Euchromatic histone-lysine N-methyltransferase 2; ERs, Estrogen receptors; EZH2, Enhancer of zeste homolog 2; FGFRs, fibroblast growth factor receptors; FLC, fluconazole; GFR, growth factor receptor; HATs, histone acetylases; HCC, hepatocellular carcinoma; HDACi, histone deacetylase inhibitor; HDACs, histone deacetylases; HGFR, hepatocyte growth factor receptor; NA: not available. NA: not available.

20 ,

 20 a dual JAKs-HDACs inhibitor based on ruxolitinib scaffold, shows potent JAKs and HDACs inhibitory activities in enzymatic assays (IC50 <10 nM for HDAC1/2/3/6; 17 nM and 75 nM for JAK1 and JAK2 respectively). In cellular assays, compound 20 shows potent anti-proliferative effects not only against various leukemia cells and hematological tumor cells (IC50: 0.15-2.16 µM), but also against several solid tumor cells (MDA-MB-231, MCF-7, HCT-116, and PC-3).

  ), dasatinib (2006), nilotinib (2007), bosutinib (2012), and ponatinib (2012). Compound 34 (Table 7) [118], a dual Bcr-Abl and HDACs inhibitor derived from approved drug dasatinib and entinostat (MS-275), shows potent inhibitory activity against both Bcr-Abl and HDAC1 (IC50 values are 17.8 nM and 800 nM respectively). In the cellular assays, compound 34 exhibits potent anti-proliferative effects against K562 and DU145 cells (IC50 values are 2.62 µM and 0.6 µM respectively), better than dasatinib (IC50 are 7.4 µM and 2.43 µM respectively) and MS-275 (IC50 are 21.3 µM and 3.75 µM respectively) alone. These results clearly indicate the advantages of developing new anticancer drugs by targeting HDAC and Bcr-Abl simultaneously.<insert Table7>

  reported a series of novel dual BRD4-HDACs inhibitors derived from (+)-JQ1, tacedinaline (CI-994), and SAHA. The representative compound 43 exhibits pan-inhibition against all BET subtypes (IC50 values ranging from 11 to 316 nM) and most of HDAC subtypes (HDAC1/2/3/6/8 IC50: 21 to 192 nM). In cellular assays, compound 43 exhibits potent anti-proliferative effects against human pancreatic ductal adenocarcinoma Capan-1 cells (IC50 = 150 nM). Further studies indicate that compound 43 significantly induces the apoptosis in Capan-1 cells at a concentration of 0.5 µM and displays a much higher apoptosis rate (63.5%) than BET inhibitor JQ1 and HDAC inhibitor SAHA used alone or in the combination. These results validate the synergistic effects of dual inhibitor 43 at the cellular levels. Further in vivo studies were conducted in a Capan-1 human pancreatic cancer xenograft mice using ip bid dosing for 21 consecutive days, compound 43 significantly inhibited tumor growth in a dose-dependent manner, with greater efficacy than JQ1 and SAHA used alone or in combination. Notably, no significant body weight loss and no obvious adverse effects were observed during the study. These data support the development of a dual inhibitor as potential treatment for the pancreatic cancer, a cancer type lack of effective therapy to date. In 2020, He et al[START_REF] Pan | Discovery of thieno[2,3-d]pyrimidine based hydroxamic acid derivatives as bromodomaincontaining protein 4/histone deacetylases dual inhibitors induce autophagic cell death in colorectal carcinoma cells[END_REF] reported a series of novel BRD4-HDACs dual inhibitors based on thieno[2,3-d]pyrimidine and hydroxamic acid. The representative compound 44 exhibits high selectivity against BRD4 and class Ⅰ HDAC (BRD4 IC50: 710 nM; HDAC1/2/3/6/8 IC50: 46 -167 nM). In cellular assays, compound 44 exhibits anti-proliferative effects in three different tumor cells (IC50 values for HCT-116, SW620 and DLD1 are 450, 1780 and 2110 nM respectively). Moreover, the anti-proliferative effects in HCT-116 cells were validated through its ability in inducing cell cycle arrest, apoptosis, autophagic cell death and suppressing IL6-JAK-STAT signaling pathways. In pharmacokinetic studies in rats, compound 44 shows good oral bioavailability (%F = 40.5%). Thus, the in vivo efficacy studies were carried out in HCT-116 xenograft mice using p.o. dosing for 17 consecutive days, compound 44 exerted excellent anti-tumor effects with TGI of 42.7% (15 mg/kg) and 68.8% (30 mg/kg) respectively. No significant body weight loss and signs of toxicity were observed. These data provide opportunities for developing therapeutic drugs targeting BET-HDACs for the treatment of colorectal carcinoma.<insert Table9>

  are close analogs of CY190602, and are characterized in enzymatic level and/or in vivo studies. For example, the dual acting agent compound 45 shows pan-HDACs inhibitory activities. In the in vivo studies in Bcr-Abl cells transplanted mice, administrating compound 45 at 300 mg/kg dose resulted in significant improvement of the animal survival. Furthermore, administrating compound 45 to human lung cancer H460 xenograft mice resulted in potent antitumor effects. DNA methyltransferases (DNMTs) are a family of enzymes catalyzing the transfer of a methyl group from S-adenosyl methionine (SAM) donor to DNA. As one of the important epigenetic modifications, DNA methylation regulates expression of genes in normal development of mammalian cells. Dysregulation in DNA methylation is connected to various cancers. Thus, inhibition of DNMTs has been validated in the clinic as cancer therapy.

  HSP90, heat shock protein 90; HEL, human erythroid leukemia; IDO1, indoleamine 2,3dioxygenase 1; IMiD, immunomodulatory drugs; iNOS, inducible nitric oxide synthase; ip, intraperitoneal; isoCA-4, iso-Combretastatin A-4; ITK, interleukin-2-inducible T-cell kinase; ITP, Inhibition of Tubulin Polymerization; JAKs, Janus kinases; LIFR, leukemia inhibitory factor receptor; LOF, loss of function; LSD1, Lysine-specific demethylase 1; MAPK, mitogenactivated protein kinase; MDM2, Mouse double minute 2 homolog; MMPs, matrix metallopeptidases; NAMPT, nicotinamide phosphoribosyltransferase; NO, Nitric oxide; NOD/SCID, nonobese diabetic/severe combined immunodeficiency; NSCLC, non-small cell lung cancer; p.o., per os; PARP, Poly (ADP-ribose) polymerase; PD-L1, programmed deathligand 1; PDX, patient-derived xenograft; PDE, phosphodiesterase; PI3K, phosphatidylinositol-3-kinase; qd, once daily; Raf, rapidly accelerated fibrosarcoma; SAM, S-adenosyl methionine;

Figure 1 .

 1 Figure 1. The approved anticancer drugs targeting HDACs.

Figure 2 .

 2 Figure 2. Conceptual formation of a dual inhibitor from a HDACi.

Table 2 .

 2 Dual inhibitors of HDACs and CK2. ; HDAC6 (8980); Anti-proliferation: Jurkat (5300); MCF-7 (9020); HCT-116 (3100); HEK293 (8410); HL-60 (4690); HL-60/adr (8400); HL-60/vinc (

  ; HeLa (1850); MDA-MB-231 (600); MDA-MB-468 (230); HT-29 (790); KG-1 (240); PC-3 (3390)

Table 6 .

 6 Dual inhibitors of HDACs and Syk.

a

  DC50 refers to the concentration at which half-maximal degradation was achieved; b EC50 refers to the concentration at which half-maximal growth inhibition was achieved. NA: not available.

Table 3 .

 3 Dual inhibitors of HDACs and RTKs.

	Structure	Derived from	IC50 (nM): enzymatic and cellular activities	PK	In vivo	Ref.

Table 7 .

 7 Dual inhibitors of HDACs and Bcr-Abl.

			IC50 (nM)
	Structure	Derived from	enzymatic		PK	In vivo	Ref.
			cellular
			Bcr-Abl (17.8);
			HDAC1 (810);
			Anti-
		dasatinib and MS-275	proliferation: K562 (2620);	NA	NA	[118]
			Hep	G2
	34		(10440); DU145
			(600)
	NA: not available.

Table 23 .

 23 Dual inhibitors of HDACs and MDM2.

	Structure	Derived from	IC50 (nM) Enzymatic cellular	PK	In vivo	Ref.

Table 25 .

 25 Dual inhibitors of HDACs and proteasome.

			IC50 (nM)
	Structure	Derived from	enzymatic	PK	In vivo	Ref.
			cellular
			HDAC1 (6900);
			HDAC6 (270);
			HDAC8 (530);
		ML16 and	Anti-
		hydroxamic	proliferation:	NA	NA	[245]
		acid	HL-60 (260.7);
	81		SEM SUP-B15r (394.2);
			(820.5)

NA: not available.

Table 26 .

 26 Dual NO donor-HDACs targeting agents.

			Structure			Derived from	IC50 (nM) cellular Enzymatic	PK	In vivo	Ref.
								NO donor motif and entinostat	No specific value obtained	NA	NA	[256]
			82
									Nitrate increase in
									HEL cell (≈11%
									@100000, 3 h;
									≈19% @100000, 5 h); HDAC1 (241);
									HDAC2 (380.5);
									HDAC3	(532);	In HEL
									HDAC4	(30);	xenograft
									HDAC6	(7.4);	mice, 100
								Phenylsulfo	HDAC8	(343);	and 120
								nylfuroxan	HDAC11 (608);	NA	mg/kg, qd	[257]
			83					and SAHA	Anti-proliferation: Hela extract (38);	p.o., 21 days, TGI:
									HEL (380); HCT-	38% and
									116 (1510); Hela	48%.
									(1550);	U937
									(3100);	3-AO
									(5840);	MDA
									(2250);	ES-2
									(1390);	KG1
									(1750)
					H 2 N	HN	O	HDAC1 (1040);
								NO donor	HDAC2	(390);
							O	motif and	HDAC3 (1220);	NA	NA	[258]
	O 2 NO	ONO 2	N	N	3 HCl	O	N H	entinostat	Vasodilator activity (290) a
			84

a EC50. NA: not available.

Table 27 .

 27 Dual inhibitors in clinical trials.

	Compound Mechanism	Cancer types		Phase	Status	Clinical trial ID
							NCT03893487;
							NCT02909777;
	Fimepinosta t (CUDC-907)	PI3K-HDACs	relapsed or refractory solid tumors, CNS tumors, or lymphoma, brain tumor; prostate cancer; large B-cell lymphoma; TNBC; thyroid cancer (terminated, Phase II); lymphoma	I/II	recruiting unless otherwise indicated	NCT02913131; NCT02674750 (completed); NCT02307240 (completed); NCT03002623 (terminated); NCT01742988
							(active, not
							recruiting).
							NCT01702285
			advanced and refractory		(terminated);
	CUDC-101	EGFR-HER2-HDAC-	solid tumors, advanced or locally advanced head and neck, gastric, breast, liver and non-small cell lung	I	completed or terminated	NCT00728793 (completed); NCT01171924 (completed);
			cancer tumors				NCT01384799
							(completed).
	Domatinosta t (4SC-202)	KDM1A-LSD-HDACs	cutaneous primary advanced malignancies, gastrointestinal malignant merkel cell carcinoma melanoma refractory, hematologic cancers, melanoma;	I/II	recruiting unless otherwise indicated	NCT03278665; NCT01344707 (completed); NCT03812796; NCT04393753; NCT04133948.
			refractory,	locally
			advanced or metastatic		NCT03903458;
			melanoma;	relapsed	/		NCT03687125
			refractory	multiple		(terminated);
	Tinostamust ine (EDO-S101)	DNA-HDACs	myeloma, diffuse large B-cell lymphoma, and hematologic malignancies; MGMT-promoter unmethylated	I/II	recruiting unless otherwise indicated	NCT02576496; NCT03452930; NCT03345485 (active, not recruiting);
			glioblastoma; solid tumors;		NCT04279938
			SCLC; leukemia; ovarian		(withdrawn due
			cancer; endometrial cancer;		to safety issues)
			soft tissue sarcoma

a GI50 the concentration that results in inhibiting cell growth by 50%. NA: not available.

Acknowledgements

This work was funded by the National Natural Science Foundation of China (81730108 and 81973635), Hangzhou Normal University startup fund (4125C5021920419), Hangzhou Normal University, School of Medicine Teaching Reform Fund (4125b30100112), Project of National Students' Platform for Innovation and Entrepreneurship Training Program (201810346040, 201910346035), Program of "Xin miao" Talents in Zhejiang Province of China (2019R426040).

SCCOHT, small cell carcinoma of the ovary, hypercalcemic type; SCLC, small cell lung cancer; SNP, sodium nitroprusside; STAT, signal transducers and activators of transcription; SyK, Spleen tyrosine kinase; TAD, trans-activation domain; TAMH, transforming growth factor-α mouse hepatocytes; TBB, tetrabromobenzotriazole; TGI, tumor growth inhibition; TNBC, triple negative breast cancer; TVI, tumor volume inhibition; VEGFRs, vascular endothelial growth factors; ZBG, zinc-binding group foretinib and tucidinostat c-Met (12.5); HDAC1 [START_REF] Santo | Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma[END_REF];

Antiproliferation: HCT-116 (540); MCF-7 (280); A549 (1080) NA NA [START_REF] Hu | Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy[END_REF] NA: not available. days efficacious [START_REF] Huang | Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) dual inhibitors as a novel strategy for the combinational treatment of leukemia and invasive fungal infections[END_REF] known JAK inhibitor [START_REF] Dymock | Preparation of dioxatriazatetracycloheptacosadecaene derivatives for use as JAK and HDAC dualinhibitors[END_REF] and SAHA JAK1 (4. NA: not available. a GI50 the concentration that results in inhibiting cell growth by 50%. NA: not available. a GI50 the concentration that results in inhibiting cell growth by 50%. NA: not available. [ [START_REF] Pinkerneil | Evaluation of the therapeutic potential of the novel isotype specific HDAC inhibitor 4SC-202 in urothelial carcinoma cell lines[END_REF][START_REF] He | Metformin and 4SC-202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma[END_REF][START_REF] Huang | Pre-clinical characterization of 4SC-202, a novel class I HDAC inhibitor, against colorectal cancer cells[END_REF][START_REF] Fu | 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells[END_REF][START_REF] Wobser | Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells[END_REF][START_REF] Hoffman | Analysis of dual class I histone deacetylase and lysine demethylase inhibitor domatinostat (4SC-202) on growth and cellular and genomic landscape of atypical teratoid/rhabdoid[END_REF] NA: not available. NA: not available. Not tested Not tested [START_REF] Tian | Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors[END_REF] NA: not available.