domain: chim sdv

text:
Benjamin Zagiel

Patricia Melnyk

Philippe Cotelle

Progress with YAP/TAZ-TEAD inhibitors: a patent review (2018-present)

Keywords: Transcriptional factors TEAD, Hippo pathway, selectivity, cancers, YAP/TAZ, NF2-deficiency

Introduction: The Hippo pathway represents a new opportunity for the treatment of cancer. Overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) or TEAD has been demonstrated in cancers and YAP mediates resistance to cancer drugs. Since 2018, the potential of this pathway has been illustrated by numerous articles and patents and the first drugs entering in clinical trial phase 1. Areas covered: This review is limited to published patent applications that have disclosed small molecule inhibitors of the YAP/TAZ-TEAD interaction. Expert opinion: The YAP/TAZ-TEAD transcriptional complex is a promising target for the treatment of cancer. Approximately thirty international patents (Used data base: Sci-finder, query: TEAD; documents: patents; period: from 2017-january 2022) that disclose TEAD transcriptional inhibitors have been filled since 2018. The mechanism of action is not always described in the patents, we can divide the drugs into three different categories: (i) external TEAD ligands; (ii) non-covalent TEAD ligands of the palmitate pocket; (iii) covalent TEAD ligands which bind into the palmitate pocket. The first molecules in clinical trial phase 1 are non-covalent TEAD ligands. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.

Introduction

The highly conserved Hippo pathway, discovered in Drosophila in 1995, controls organ size and cell differentiation through the regulation of cell proliferation, apoptosis and stem cell function [START_REF] Justice | The Drosophila Tumor Suppressor Gene Warts Encodes a Homolog of Human Myotonic Dystrophy Kinase and Is Required for the Control of Cell Shape and Proliferation[END_REF]. Growing interest in the Hippo pathway has been firstly driven by its deregulation in many diverse cancers as reported in many reviews, [START_REF] Moroishi | The Emerging Roles of YAP and TAZ in Cancer[END_REF][START_REF] Zanconato | YAP/TAZ at the Roots of Cancer[END_REF] then found interest in regenerative medicine [START_REF] Johnson | The Two Faces of Hippo: Targeting the Hippo Pathway for Regenerative Medicine and Cancer Treatment[END_REF][START_REF] Moya | Hippo-YAP/TAZ Signalling in Organ Regeneration and Regenerative Medicine[END_REF][START_REF] Dey | Targeting the Hippo Pathway in Cancer, Fibrosis, Wound Healing and Regenerative Medicine[END_REF] to finally emerged in the field of neurodegenerative diseases. [START_REF] Sahu | The Emerging Role of Hippo Signaling in Neurodegeneration[END_REF][START_REF] Jin | The Effects of YAP and Its Related Mechanisms in Central Nervous System Diseases[END_REF] The Hippo pathway is mainly composed of a series of kinases which after stimulation by upstream signals including metabolic regulators [START_REF] Piccolo | The Biology of YAP/TAZ: Hippo Signaling and Beyond[END_REF][START_REF] Koo | Interplay between YAP/TAZ and metabolism[END_REF] causes the YAP (Yes-Associated Protein) /TAZ (transcriptional co-activator with PDZ-binding motif, also known as WWTR1 (WW domain-containing transcription regulator protein 1) phosphorylation to remain in the cytoplasm, eventually leading to its capture and degradation. Unphosphorylated YAP/TAZ enters the nucleus and promotes downstream genes expression through the formation of transcriptional complexes mainly with TEAD1-4 transcription factors which are considered as the most important output of the Hippo pathway.

Figure 1:

The Hippo pathway YAP and TAZ bind to TEAD1-4 to drive expression of numerous target genes including CTGF, Cyr61 or Axl (cell proliferation), Survivin (Birc-5) (inhibition of apoptosis), Sox2, Nanog and Oct4 (stemness, pluripotency). Besides YAP/TAZ, the most studied coactivators of TEAD1-4 transcriptional activity, the Vestigial-like (VGLL) protein family, which consists in four members (VGLL1-4), has been shown to interact with TEAD to regulate distinct gene expression. [START_REF] Yamaguchi | Multiple Roles of Vestigial-Like Family Members in Tumor Development[END_REF] Although VGLL1-4 bind to the YAP/TAZ binding domain of TEAD1-4, VGLL1-3 and VGLL4 have distinct molecular functions and only VGLL4 has been reported to inhibit YAP/TAZ-TEAD interactions.

YAP/TAZ and TEADs form a complex through the interaction of the N-terminal domain of YAP (or TAZ) and the C-terminal domain of TEAD. Li et al. [START_REF] Li | Structural Insights into the YAP and TEAD Complex[END_REF] (Figure 2) defined the three interfaces of contact between TEAD1 209-426 and YAP 50-171 and their respective importance in the binding as follows: interface 3 (in light green on Figure 2A) > interface 2 (in plum) > interface 1 (in hot pink). The smaller fragment of YAP or TAZ which gives a nanomolar range binding constant corresponds to interfaces 2 and 3, [START_REF] Hau | The TEAD4-YAP/TAZ Protein-Protein Interaction: Expected Similarities and Unexpected Differences[END_REF] but mVGLL1 27-56 was found to be equivalent to YAP and TAZ although VGLL do not interact with TEAD at the interface 3. [START_REF] Bokhovchuk | Molecular and Structural Characterization of a TEAD Mutation at the Origin of Sveinsson's Chorioretinal Atrophy[END_REF] Interfaces 2 and 3 correspond to the external predicted druggable sites in plum and light green (Figure 2B). [START_REF] Gibault | Targeting Transcriptional Enhanced Associate Domains (TEADs)[END_REF] In 2016, was reported for the first time, that C-terminal domain of TEAD2 and TEAD3 are palmitoylated in an internal hydrophobic pocket. [START_REF] Chan | Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of the Hippo Pathway[END_REF]17] This internal pocket clearly appears as the third druggable site of TEAD (in light blue, Figure 2B). Dysregulation of the Hippo pathway may occur in many diseases, including cancers, neurodegenerative diseases and rare diseases. YAP/TAZ phosphorylation regulates many hallmarks of cancer, including cancer cell proliferation, cancer stem cell fate, chemoresistance and metastasis. Elevated levels as well as the nuclear localizations of YAP/TAZ are observed in many human cancers where they are correlated with poor prognosis. The activation of YAP or TAZ in the majority of these cancers is not associated with mutations in Hippo pathway components [START_REF] Moroishi | The Emerging Roles of YAP and TAZ in Cancer[END_REF][START_REF] Johnson | The Two Faces of Hippo: Targeting the Hippo Pathway for Regenerative Medicine and Cancer Treatment[END_REF][START_REF] Moya | Hippo-YAP/TAZ Signalling in Organ Regeneration and Regenerative Medicine[END_REF][START_REF] Dey | Targeting the Hippo Pathway in Cancer, Fibrosis, Wound Healing and Regenerative Medicine[END_REF], except for hepatocellular carcinomas [START_REF] Lam-Himlin | The hippo pathway in human upper gastrointestinal dysplasia and carcinoma: a novel oncogenic pathway[END_REF] uveal melanoma [START_REF] Menzel | In melanoma, Hippo signaling is affected by copy number alterations and YAP1 overexpression impairs patient survival[END_REF], mesotheliomas [START_REF] Fujii | TGF-beta synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth[END_REF], neurofibrosarcomas [START_REF] Wang | TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells[END_REF], pancreatic ductal adenocarcinomas [START_REF] Mueller | Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes[END_REF] and glioblastomas [START_REF] Lee | Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p[END_REF] that can have genomic amplifications of YAP or TAZ and somatic mutations in components of the Hippo pathway. Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities. MM is usually diagnosed at advanced stages, surgery is no longer an option and conventional combination chemotherapy only extends the median overall survival for a few months. As many targeted therapies tested in clinical trials for this aggressive cancer without success, new therapeutics such as targeting YAP/TAZ-TEAD is highly pertinent in NF2-deficient or NF2-mutant mesotheliomas [START_REF] Sekido | Targeting the hippo pathway is a new potential therapeutic modality for malignant mesothelioma[END_REF].

Patent evaluation

The database sci-finder (https://scifinder-n-cas-org/) has been queried (TEAD inhibitors/TEAD ligands) and the patent abstracts have been collected. We limited our study on international patent applications and analyzed the abstracts. The patents have been collected at the espacenet web site (https://worldwide.espacenet.com). During the manuscript revision, we repeated the procedure. We finally analyzed 29 patent applications covering from 2017-january 2022 period. For an overview, TEAD patent applications discussed in this article are summarized in Table 1. When known, the reported drugs are classified into three different classes (external ligands, non-covalent internal pocket ligands and covalent internal pocket ligands). In 2016, the presence of palmitate in an internal pocket of hTEAD2 or hTEAD3 was reported for the first time, which seems to increase the stability of the TEAD protein. [START_REF] Chan | Autopalmitoylation of TEAD Proteins Regulates Transcriptional Output of the Hippo Pathway[END_REF] At the same time, Wu et al.

disclosed the discovery of MGH-CP-1 (Figure 3), a ligand of TEAD which crystallized in the TEAD internal pocket (PDB code of the crystal structure: 6CDY). [START_REF] Li | Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription[END_REF] The main structural characteristics of the patented compounds (WO2017053706A1) [START_REF] General | TEAD transcription factor autopalmitoylation inhibitors[END_REF] are the presence of an adamantyl group and a thiotriazole heterocycle at both ends mimicking the lipophilic and hydrophilic parts of fatty acids. Details concerning the patent are given in the previous patent review. [START_REF] Crawford | Hippo pathway inhibition by blocking the YAP/TAZ-TEAD interface: a patent review[END_REF] Following this first patent, the authors replaced the terminal heterocycle (triazole) by the more classical structure of flufenamic acid (CP-58) to yield CP-55 which presents submicromolar activities on cell proliferation assays (92.1 (uveal melanoma) and Huh7 (liver carcinoma) cell lines). Dana Farber Cancer Institute patented in three international patents two large families of di or tri substituted aromatics bearing reactive motifs. In the first patent (WO2020081572A1), [START_REF] Farber | Transcriptional Enhanced Associate Domain (TEAD) Transcription Factor inhibitors and uses thereof[END_REF] these reactive motifs are acryloyl and chloroacetyl groups linking to an non aromatic heterocyclic nitrogen atom (see Figure 4). In this first patent, the compounds were firstly evaluated on a TEAD transcription reporter assay (8xGTIIC) and then on the endogenous TEAD targets (Axl, CTGF, Cyr61 and Survivin) in MDA-MB-231 cell lines. While the structure of MYF-01-037 (Figure 4) is protected in the first patent, the most of the data published by Kurppa et al. [START_REF] Kurppa | Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway[END_REF] is reported in the second patent (WO2021133896A1). [START_REF] Farber | Transcriptional Enhanced Associate Domain (TEAD) Transcription Factor inhibitors and uses thereof[END_REF] MYF-01-037 inhibits YAP/TEAD interaction in HEK293T cells (IC50 = 0.8 µM) and reduced CTGF expression in PC-9 cells while it has roughly no effect on PC-9 transfected with TEAD1 C359S mutant which attests its target is effectively the palmitate pocket and its highly conserved cysteine residue. Ultimately, co-targeting EGFR, MEK and YAP/TEAD was applied on EGFRmutant NSCLC to overcome the treatment-induced tumor dormancy through Hippo pathway. The authors claimed the global structure is directly inspired from the NSAID flufemamic acid with the 3-trifluoromethylaniline motif and the following patents reported mainly di or trisubstituted aromatic rings (WO2021133896A1)(compounds I-A-02 and II-1)(Figure 5) with one of the substituant being an heteroaryl ring (WO2021247634A1) [START_REF] Farber | Transcriptional Enhanced Associate Domain (TEAD) Transcription Factor inhibitors and uses thereof[END_REF] (compounds A-21 and A-16) (Figure 5). The IC50 of these compounds were measured in an anti-proliferation assay on NCI-H226 cells for 5 days and are in the micromolar range (compounds I-A-02 and II-1) and in the nanomolar range (compounds A-21 or A-16). Bum-Erdene et al. [START_REF] Bum-Erdene | Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction[END_REF] reported a small molecule (TED-347)(Figure 6) inhibiting YAP-TEAD complex transcriptional activity through the presumed formation of a covalent bond with the cysteine residue in the central pocket. The X-ray data are given but the electron density seems to us to correspond to palmitate. Using fluorescence polarization experiments, the authors were able to measure the inhibitory activity of their compounds for the YAP/TEAD4 interaction. TED-347 possessed an EC50 of 5.9 µM and a similar IC50 in a HEK293 cell-based assay but was found to be toxic in EGFR-mutant NSCLC cell [START_REF] Kurppa | Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway[END_REF] lines. TED-347 is part of a patent [START_REF]Compounds and Methods to Attenuate Tumor Progression and Metastasis[END_REF] which cover general structure reported on Figure 6. Inventiva was the first company who protected its YAP/TAZ-TEAD inhibitors and the first patent [START_REF] Inventiva | New Compounds Inhibitors Of The YAP/TAZ-TEAD Interaction And Their Use In The Treatment Of Malignant Mesothelioma[END_REF] has been previously reviewed. [START_REF] Crawford | Hippo pathway inhibition by blocking the YAP/TAZ-TEAD interface: a patent review[END_REF] The protected structures correspond to diversely substituted benzo[d]isothiazole-1,1-dioxide (Figure 7) on which is branched at position 3 a N-susbtituted vanilline hydrazone motif. The following patent [START_REF] Inventiva | New Compounds Inhibitors Of The YAP/TAZ-TEAD Interaction And Their Use In The Treatment Of Malignant Mesothelioma[END_REF] is an extension of this first patent where the 4-hydroxy-3methoxybenzylidene motif is replaced by disubstituted methylene motif yielding to the identification of phenylboronic acid and ester moieties (Ex 92 and Ex 96). Finally the most recent patent [START_REF] Inventiva | Inhibitors Of The YAP/TAZ-TEAD Interaction And Their Use In The Treatment Of Cancer[END_REF] explored the replacement of benzo[d]isothiazole-1,1-dioxide heterocycle by various fused heterocycles (Ex 96).

The compounds were tested on a transcient transactivation assay on HEK293 cells using plasmids of hTEAD1, YAP mutant (S127A, S397A) and a luciferase reporter. The lowest IC50 are at a submicromolar level. The tumor cell growth inhibitory activity of the YAP-TEAD inhibitors was tested on NCI-H2052 cell line, a mesathelioma cell line harboring a NF2 mutation. Best compound (Ex 118) exhibits an nanomolar IC50 on NCI-H2052 cell line without showing any effect on Met5A cell line (a YAP independent mesothelioma cell line). The best compound of the first patent (Ex It acts also synergistically with 5-FU in inhibiting growth of esophageal adenocarcinoma in vivo. [START_REF] Song | A Novel YAP1 Inhibitor Targets CSC-Enriched Radiation-Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma[END_REF] Extension of this patent on 2,7-disubstituted-9H-fluorene-9-one oxime was applied by Vivace Therapeutics in 2017. [START_REF] Therapeutics | Tricyclic compounds[END_REF] Since 2018, Vivace Therapeutics has deposited seven recent patent applications, [START_REF] Therapeutics | Non-Fused Tricyclic Compounds[END_REF][START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF][START_REF] Therapeutics | Benzocarbonyl Compounds[END_REF][46][START_REF] Therapeutics | Bicyclic compounds[END_REF][START_REF] Therapeutics | Bicyclic Compounds[END_REF][START_REF] Therapeutics | Heteroaryl compounds[END_REF] and their lead molecule VT-3989 enters in phase 1 clinical trial (NCT04665206) in early 2021 (https://clinicaltrials.gov/ct2/show/NCT04665206). It is evaluated in patients with metastatic solid tumors enriched for tumors with NF2 gene mutations. Two distinct families have been patented. The first one is inspired from the flufenamic acid structure [START_REF] Therapeutics | Non-Fused Tricyclic Compounds[END_REF][START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF][START_REF] Therapeutics | Benzocarbonyl Compounds[END_REF][46][START_REF] Therapeutics | Heteroaryl compounds[END_REF] and the biological data of VT-103 [START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF] (Figure 8) have been detailed in a recent article. [START_REF] Tang | Small Molecule Inhibitors of TEAD Auto-Palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-Deficient Mesothelioma[END_REF] Thermal shift assay on the four TEAD family members suggested a selectivity of VT-103 for TEAD1, which was confirmed by a TEAD palmitoylation assay. VT-103 inhibits cell proliferation of a panel of NF2-deficient mesothelioma cell lines at low nanomolar IC50. VT-103 was evaluated in two malignant mesothelioma tumor xenograft mouse models with impressive outcomes, including an NCI-H226 model with TGI = 106% at 3 mg/kg p.o. and an NCI-H2373 model with TGI = 126% at 10 mg/kg p.o. Favorable pharmacokinetics profile in mice VT-103 is also reported in this article. The second patented family consists of a substituted bicyclic aromatic ring, exemplified by VT-104 structure. [START_REF] Therapeutics | Bicyclic compounds[END_REF][START_REF] Therapeutics | Heteroaryl compounds[END_REF] VT-104 is part of the second family of substituted bicyclic aromatics substituted with an amide functional group. VT-104 is a pan-TEAD binder (TSA and palmitoylation assay), with low nanomolar IC50 values in proliferation. Crystal structure (PDB: 7CNL) of VT-105 in the TEAD3 internal pocket confirms the mode of action of this family. VT-104 also exhibits a favorable pharmacokinetics profile and a high efficacy on xenograft mice. The importance of the chirality is highlighted with the absence of biological activities of VT-106 compared to VT-107.

Genentech

Genentech released patent WO2019232216A1 [START_REF] Genentech | Therapeutic compounds[END_REF] including 46 examples derived from the following general structure (Figure 9) as inhibitors of the YAP-TEAD interactions and therefore potential drugs to be used in YAP-TEAD mediated pathologies such as cancer. The general structure is composed of a pyrazolo[1,5-a]pyrimidin-7(4H)-one core bearing several substituents in position 2, 3 and 5. Position 2 can be substituted by halogens and (halo)alkyl chains. Position 3 bears an ester or an amide with chains covering various (cyclo)alkyl or (hetero)aryl. Position 5 bears a substituted (hetero)aryl moiety.

The compounds were evaluated in a TR-FRET binding assay on TEAD2217-447 or TEAD3217-447. The compounds demonstrating the best results are represented on Figure 9. They share structural similarities as for the three of them position 2 is unsubtituted, position 3 bears a fluoromethyl or cyano substituted azetidine/pyrrolidine amide and position 5 is a paracyclohexylphenyl fragment. The three of them were found to have similar affinity for TEAD2 with EC50 values from 4.5 to 8.8 nM and for TEAD3 with EC50 around 10 nM except for compound 37 for which it proved to be quite higher.

In patent WO2020051099A1, [START_REF] Genentech | Carboxamide and Sulfonamide Derivatives Useful as TEAD Modulators[END_REF] Genentech reported two general structures (and 57 examples). The first one is centered around a variously polysubstituted six-membered aromatic/heteroaromatic ring bearing halo, cyano, alkyl, cycloalkyl, alkylcycloalkyl, haloalkyl or O-alkyl group. The compounds were evaluated as TEAD lipid pocket binders in a TEAD lipid assay followed by fluorescence polarization. A TEAD reporter activity inhibition assay performed on Detroit 562 cells (pharingeal carcinoma) is also mentionned but the results are not to be included in the patent. Compound 58 (Figure 10) was found to have the best affinity for all TEADs with IC50 values ranging from 8 to 34 nM. Noticeably, it features a reactive vinylsulfonamide moiety as a Michael acceptor group. Compound 57B (Figure 10) also demonstrated a quite good affinity for TEAD2 and TEAD4 (respectively 17 and 19 nM) but substantially less for TEAD1 and TEAD3 (respectively 128 nM and 298 nM) maybe due to a better selectivity towards TEAD2/4 than TEAD1/3. Detailed biological and biophysical properties of compound 58 have been disclosed in [START_REF] Holden | Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling[END_REF]. Although it inhibits TEAD palmitoylation by replacing palmitate in the internal pocket (PDB code: 6UYC), its mechanism of action could due in vivo (Detroit X1 562 xenograft model) by transforming TEAD into the dominant negative transcriptional repressor which blocks the TEAD interaction with chromatin.

In patent WO2021097110A1 [START_REF] Genentech | Therapeutic compounds and methods of use[END_REF] the protected general stucture overlaps with the previous patent as it is derived from the best compounds previously identified. The 2-methoxy or 3-methoxypyridine is conserved for a majority of the compounds and variations are explored for the terminal group of the alkenyl chain, the chain in itself and other substitutents on the ring as well. Most importantly, the vinylsulfonamide moiety in compound 58 and the amide chain in compound 57B are now replaced with an optionnaly substituted acrylamide moiety, urea moiety or oxirane moiety. A few examples explore different core ring such as pyrimidine, dihydrobenzofurane, quinoline, 1,6-naphthyridine, benzoxazole and benzothiazole but keep the substitutents pointing in the same general directions.

The compounds were evaluated in a biophysical TR-FRET assay and compounds 53, 54 and 55 (Figure 11) were found to be the best TEAD2 and TEAD4 lipid pocket binders with IC50 in the nanomolar range. In patent WO2022020716A1 [START_REF] Genentech | Heterocyclic compounds as inhibitors of TEAD for treating cancer and their preparation[END_REF], the authors extended the previous one where the anilinic nitrogen is substituted by acrylic acid moiety.

Patent WO2021108483A1 [START_REF] Genentech | Therapeutic compounds[END_REF] presents a second generation of compounds based on the structure of compound 41 from patent WO2019232216A1. [START_REF] Genentech | Therapeutic compounds[END_REF] The second generation explores several modulations : the position 2 of the core platform is substituted with heterocycles, hydroxylated chains and amides, the apolar cyclohexyl group is modulated by other lipophilic fragments and further substitution of the azetidine/pyrrolidine cycle is also investigated.

The compounds were evaluated in a TR-FRET binding assay using all TEAD1/2/3/4 and biotinylated YAP50-100 and TAZ13-57. The best inhibitors (Figure 15) demonstrated nanomolar EC50 for all the YAP or TAZ/TEAD1-4 except compound 70 which is selective of TEAD1,2,3 vs TEAD4. They all bear a pyrimidine or pyrazine heterocycle at the position 2 of the core structure. The phenyl in position 5 is parasubstituted with a mehtylcyclopentane moiety or a 9 carbon chain. It appeared that the second generation of compounds did not show higher potency than the best hits from the first one at inhibiting the YAP/TAZ-TEAD interaction. In the continuity of patent WO2020051099A1, [START_REF] Genentech | Carboxamide and Sulfonamide Derivatives Useful as TEAD Modulators[END_REF] patent WO2021178339A1 [START_REF] Genentech | Heterobifunctional molecules as TEAD inhibitors[END_REF] presents heterobifunctional compounds derived from 57B as TEAD inhibitors. The structure of 57B is conserved but the terminal N-Me amide is replaced by a linker chain (carbon or PEG of variable length). The scope of this patent also extend to modifications of the linked structures. The compounds were evaluated in a biophysical TR-FRET assay. The authors pointed out the fact that the TR-FRET format allows more sensitive determination of affinity for the lipid pocket than the fluorescence polarization assay thanks to a lower concentration of TEAD protein for this test. Compound 17 was found to be the best TEAD lipid pocket binder with IC50 values as low as 0.04 µM for TEAD4 and 0.09 µM for TEAD2. Affinities for TEAD1 and especially TEAD3 were quite weaker. Noticeably, all the tested comounds showed poorer affinity for TEAD3 as 17 proved to have the lowest IC50 of all the tested compounds (1.50 µM). The compounds are constituted of two rings A and B connected with a linker L1. Both A and B cycles can either be a phenyl group, a saturated or partially unsaturated carbocyle or heterocycle with 1 or 2 heteroatoms, an heteroaromatic ring with 1 to 4 heteroatoms (5-or 6-membered), a bicyclic aromatic or heteroaromatic ring with 1 to 5 heteroatoms (8-or 10-membered). The L1 linker is a C1 to C6 linear or branched chain in which one to three CH2 can be replaced by a connecting group (ether, thioether, amine, ketone, ester, amide, carbamate, urea, sulfoxide, sulfone, sulfonamide, thioketone, thionoester, thioamide or thiourea). When B cycle is a phenyl motif, it can be tetrasubstituted by various substituents. The patents present the results of an inhibition of TEAD reporter activity assay for certain compounds. The assay was conducted in MCF-7 TEAD reporter cells as well as H226 and H28 mesothelioma cell lines. Focusing on the TEAD reporter assay, a total of 67 compounds demonstrated EC50 below 0.1 µM.

The authors state that isomer 2 of compound I-12 (Figure 17) demonstrated inhibition of cell proliferation for NF2 mutant cell lines in particular and no effect seemed to be detectable on H28 cell line (non-deficient NF2 cell line). The compound showed EC50 < 0.2 µM for the following cell lines: MSTO211H (biphasic mesothelioma), NCI-H1975 and NCI-H2085 (adenocarcinoma), NCI-H2052 and NCI-H226 (mesothelioma), SNU182 (hepatocellular carcinoma), U251 (glioblastoma) and YD8 (squamous cell carcinoma). Isomer 2 of I- Chène's team (from Novartis Oncology) largely contributes to a better understanding on the interaction between the C-terminal domain of TEAD and its co-factors (YAP, TAZ, VGLL and FAM) and published 12 articles and 17 crystal structures of wild-type or mutant hTEAD1 or 4. This team designed of potent peptide inhibitors of the YAP-TEAD interface 3. [START_REF] Furet | Structure-Based Design of Potent Linear Peptide Inhibitors of the YAP-TEAD Protein-Protein Interaction Derived from the YAP Omega-Loop Sequence[END_REF] Very recently, Novartis patented biaryl derivatives (WO2021186324A1) [START_REF] Novartis | Biaryl Derivatives as YAP/TAZ-TEAD Protein-Protein Interaction Inhibitors[END_REF] as inhibitors of the protein-protein interaction between YAP/TAZ and with a total of 176 examples of biaryl compounds (Figure 19). The compounds are constituted of a central biaryl core with the first aryl being a phenyl (X = CH) or pyridinyl (X = N) ring substituted with R1, R2 and R3. R1 subtitutents range from simple hydrogen and halogens to alkyl, O-/NH-/S-alkyl with various substitutions on the alkyl chains (halo, hydroxy, alkoxy, carboxyl, morpholine and heterocycles). R2 is either hydrogen or methyl but also fluorine and chlorine. R3 covers a variety of rather polar groups such as nitrile, carboxamide, alkyl esters, carboxylic acid, alkyl/aryl-substituted amide, alkyl-substituted amine and O-hydroxyalkyl.

The second aryl moiety is generally a substituted 2,3-dihydrobenzofurane derivative (Z = O) but can be an indoline derivative (Z = NH) or an indane derivative (Z = CH2). On this moiety, R4 is generally a chlorine atom but can also be other halogens, halogenated alkyl chains or a cyano group. R5 is either a hydrogen atom or an halogen atom. The position 2 of the five-membered ring is substituted with an aromatic or heteroaromatic ring that can optionnaly bear halo or haloalkoxy substituents. The same position 2 also holds a nitrogen bearing group (R6 = NH2, alkylamine or cycloalkylamine). Finally, the position 3 on the five membered ring, when substituted (R7) , can bear alkyl, hydroxyalkyl or alkoxyalkyl chains.

The compounds were evaluated in a biochemical TR-FRET.

[62] The results show that most of the compounds are able to inhibit the interaction between hTEAD4217-434 and hYAP60-100 with IC50 in the low nanomolar range. 134 compounds demonstrated IC50 < 10 nM and amongst them 5 demonstrated IC50 < 1 nM.

The compounds were also tested in two in vitro cellular assays. First, a luciferase-based reporter gene assay was conducted in NCI-H2052 mesothelioma cells in order to monitor YAP-dependent pathway activity. MKN-45 gastric adenocarcinoma cells (YAP-deleted) with constitutive luciferase expression were used as a specificity control. The same cell lines were used in a proliferation assay.

The two compounds showing the best activities in both tests are represented in Figure 12. They both demonstrated similar IC50 values (respectively 10 nM for example 144 and 11 nM for example 147) as well as GI50 values (respectively 10 nM for example 144 and 5 nM for example 147). Structurally, they share the same susbtituent pattern with R1 = OMe, R2 = F, R3 = CONH2 on the phenyl part of the biaryl and R4 = Cl, R5 = F and R6 = NHMe. Their sole difference lies with = Me (144) or CH2OH (147).

Novartis has initiated a phase I clinical study with IAG933 (structure not disclosed) (NCT04857372)( https://clinicaltrials.gov/ct2/show/NCT04857372). The purpose of that study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2-mutated tumors compared to tumors with functional YAP/TAZ and to identify the maximum tolerated dose.

Sanofi

Sanofi patented (WO2021204823A1) [START_REF] Sanofi | Preparation of (1H-indol-5-yl)acrylamide derivatives as inhibitors of TEAD proteins and the hippo YAP/TAZ signaling cascade for the treatment of cancer[END_REF] 1H-indolyl-acrylamide derivatives (general structure depicted on Figure 20).

Figure

General patented structure [START_REF] Sanofi | Preparation of (1H-indol-5-yl)acrylamide derivatives as inhibitors of TEAD proteins and the hippo YAP/TAZ signaling cascade for the treatment of cancer[END_REF][START_REF] Sanofi | Preparation and anticancer activity of acrylamide-substituted indanes[END_REF] and structure of the most active compounds

The core indole platform was conserved while various substituents at the indole nitrogen atom were incorporated. The scope encompassed benzyl, phenyl, alkyl and cycloalkyl chains, pyridinyl fragments and five-membered ring heterocycles. The acrylamide moiety was placed at the position 5 of the indole. The position of the acrylamide moiety was also modulated at the position 4, 6 or 7 of the indole ring.

The compounds were tested in a luciferase-based gene reporter assay to monitor YAP1-TEAD and TAZ-TEAD activity and investigate modulation of these activities in different human tumor cell lines with IC50 ranging from 1 nM to 10 M. The authors indicated that most of the compounds had IC50 values less than 1 M and particularly between 1 and 100 nM. Figure 20 shows the structures of the compounds with the best activities. The 5-acrylamide indole platform is substituted by a (4-trifluoromethyl)phenyl moiety on the nitrogen atom and can either be unsubstituted or bear a methyl group in position 2 or 3 of the indole ring.

In a more recent patent (WO2022023460A1) [START_REF] Sanofi | Preparation and anticancer activity of acrylamide-substituted indanes[END_REF], the indole motif has been replaced by an indane bicycle with an IC50 of 72 nM for the example reported on Figure 20.

Merck

Merck Patented (WO2021224291A1) [START_REF] Merck | Tricyclic heterocycles useful as TEAD binders and their preparation[END_REF] and (WO2022018072A1) [START_REF] Merck | Preparation of tricyclic heterocycles for treating or preventing conditions affected by inhibiting YAP-TEAD and/or TAZ-TEAD interaction[END_REF] a very large family of tricyclic heterocycles of formula depicted in Figure 21.

YAP-TEAD interaction inhibition was measured using a 8 x TEAD responsive elements driving the nanoLuc® luciferase gene on SK-HEP-1 cells (hepatocarcinoma). Viability assays were conducted on NCI-H226 mesothelioma (YAP-dependent) and on SW620 YAP KO colorectal (YAP-independent) cells.

Best results were obtained with 4-aryl-pyrazolo, oxazolo, thiazolo or triazoloindole-7-carboxylic acids were the aryl group is substituted at para position by a trifluoromethyl group (IC50 on SK-HEP-1 cells in the range of 1 nM to nM; IC50 on NCI-H226 cells in the range of 1 nM to 100 nM; IC50 on SW620 YAP KO cells in the range > 30 µM). Conversely to the other pharmaceutical companies, Astra-Zeneca appears in the field of activators of YAP/TAZ-TEAD interaction through collaborations with academics (Max Planck Institute for Molecular Physiology, Dortmund, Germany and A*STAR Institute of Molecular and Cell Biology, Singapore, Singapore mainly). While most reported palmitate pocket binders show inhibitory activity on TEAD palmitoylation and transcription, quinolinols were found to stimulate TEAD activity.

[67] Q2 (Figure 22) is supposed to occupy the TEAD central pocket as shown by SPR (Surface Plasmon Resonance) on wt-hTEAD2 compared to A231I mutant and increase expression levels of CTGF, CYR61 and ANKRD1. In vivo, quinolinol Q2 accelerates cutaneous wound healing in mice to as soon as day 7.

In another article, [68] the same collaboration between Astra-Zeneca and academics led to the design of an eicosapeptide 4E (Figure 22) (derived from the VGL4 233-252 amino acid sequence by D to E replacement leading to crosslinked via lactamization of residues E235 and K250) linked to Tat sequence through a PEG2 linker presents a crosslink between the acid function of a glutamic residue and the ammonium function of a lysine residue. It binds to mTEAD4 (PDB code: 6SBA) at the interface 2 as previously published YAP/TAZ-TEAD inhibitors [START_REF] Sturbaut | Discovery of a cryptic site at the interface 2 of TEAD -Toward new anti-cancer compounds[END_REF] but was found higher inhibitor of VGLL4 than YAP and therefore activates YAP-TEAD interaction, increases mRNA target genes levels (CYR61, CTGF, ANKRD1 and SEPINE1) in human cardiomyocytes and accelerates wound healing of RKO cells.

Expert opinion

In term of chemical structure, this review showed a large structural diversity with the omnipresence of fenamate family, including flufenamic acid and its trifluoromethyl group which appears in a large majority of YAP/TAZ-TEAD inhibitors, that have been firstly identified by Pobbati et al. [START_REF] Pobbati | The Novel Potent TEAD Inhibitor, K-975, Inhibits YAP1/TAZ-TEAD Protein-Protein Interactions and Exerts an Anti-Tumor Effect on Malignant Pleural Mesothelioma[END_REF] in 2015 as TEAD ligand occupying the internal pocket. The use of covalent warhead (chloroacetamide, acrylamide and vinylsulfamide) is also abondantly documented giving raise to high affinity in in vitro assay but not always translated as well in cellulo assays maybe due to problematic selectivity.

With the first articles published in 2010 on the crystal structures of YAP-TEAD [START_REF] Mueller | Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes[END_REF] in hand, medicinal chemists firstly looked at disrupting interaction and it was successful with modified peptides [START_REF] Furet | Structure-Based Design of Potent Linear Peptide Inhibitors of the YAP-TEAD Protein-Protein Interaction Derived from the YAP Omega-Loop Sequence[END_REF][START_REF] Pobbati | Identification of Quinolinols as Activators of TEAD-Dependent Transcription[END_REF] but not with small molecules (with the exception of substituted pyrazoles). [START_REF] Merck | Preparation of tricyclic heterocycles for treating or preventing conditions affected by inhibiting YAP-TEAD and/or TAZ-TEAD interaction[END_REF] Several compounds [START_REF] Bum-Erdene | Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction[END_REF]71] proved to interact with TEAD at the internal pocket and competed with palmitate and the use of covalent warhead was justified by the existence of a conserved cysteine at the entry of the palmitate pocket which was found to be linked to the fatty acid by a thioester bond.

[24] However, it is not the real purpose of a patent to determine the mechanism of action and we refered here to the numerous available crystal structures of TEAD with ligands in its internal pocket.

Ex 22 patented by Inventiva, [START_REF] Inventiva | New Compounds Inhibitors Of The YAP/TAZ-TEAD Interaction And Their Use In The Treatment Of Malignant Mesothelioma[END_REF] has been demonstrated to bind at the interface 3 of TEAD1 as measured by fluorescence polarization assay showing that it is able to compete with YAP (TMR-YAP84-100) but litterature showed that internal pocket ligands may be found to inhibit YAP-TEAD in vitro by fluorescence polarization assay (using FAM-YAP60-99 or FITC-YAP50-100) [START_REF] Bum-Erdene | Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction[END_REF][START_REF] Karatas | Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket[END_REF] or in cells (Split gaussia luciferase assay or co-IP) [START_REF] Kurppa | Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway[END_REF][START_REF] Tang | Small Molecule Inhibitors of TEAD Auto-Palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-Deficient Mesothelioma[END_REF] while other ligands have not effect on the YAP-TEAD interaction (TR-FRET or FP assay (using FITC-YAP61-100). [START_REF] Holden | Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling[END_REF][START_REF] Lu | Discovery and Biological Evaluation of Vinylsulfonamide Derivatives as Highly Potent, Covalent TEAD Autopalmitoylation Inhibitors[END_REF] Specific dysregulation of TEAD in cancers is well-documented. TEAD1 is mainly implicated in prostate, cervical and breast cancers [START_REF] Malt | Alteration of TEAD1 Expression Levels Confers Apoptotic Resistance through the Transcriptional Up-Regulation of Livin[END_REF][START_REF] Knight | TEAD1 and C-Cbl Are Novel Prostate Basal Cell Markers That Correlate with Poor Clinical Outcome in Prostate Cancer[END_REF] whereas TEAD2 is a novel prognostic factor for hepatocellular carcinoma. [START_REF] Joo | TEAD2 as a Novel Prognostic Factor for Hepatocellular Carcinoma[END_REF] TEAD2 expression is increased during epithelial-mesenchymal transition in breast cancer cells [START_REF] Diepenbruck | Tead2 Expression Levels Control the Subcellular Distribution of Yap and Taz, Zyxin Expression and Epithelial-Mesenchymal Transition[END_REF] and it was found to be an independent prognostic factor in pancreatic ductal adenocarcinoma [START_REF] Drexler | Association of Subcellular Localization of TEAD Transcription Factors with Outcome and Progression in Pancreatic Ductal Adenocarcinoma[END_REF] and NF-2 controls the invasiveness through YAP-TEAD2-dependent expression of Cyr61 in glioblastoma. [START_REF] Lee | Neurofibromatosis 2 (NF2) controls the invasiveness of glioblastoma through YAP-dependent expression of CYR61/CCN1 and miR-296-3p[END_REF] TEAD4 is implicated in colorectal cancer [START_REF] Liu | Increased TEAD4 Expression and Nuclear Localization in Colorectal Cancer Promote Epithelial-Mesenchymal Transition and Metastasis in a YAP-Independent Manner[END_REF] and in hepatoblastoma [START_REF] Zhang | Vestigial like Family Member 3 Is a Novel Prognostic Biomarker for Gastric Cancer[END_REF] and elevated levels of a splicing isoform of TEAD4 associated with an increased rate of survival was also reported in cancer patients. [START_REF] Qi | Splicing Isoform of TEAD4 Attenuates the Hippo-YAP Signalling to Inhibit Tumour Proliferation[END_REF] For these reasons, selectivity towards one member of the TEAD family found great interest in the context of personalized medicine. Vivace Therapeutics reported the first selective TEAD1 ligand [START_REF] Tang | Small Molecule Inhibitors of TEAD Auto-Palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-Deficient Mesothelioma[END_REF] and Genentech reported selective TEAD2/4 ligands that found great interest in specific TEAD deregulated cancers. Nevertheless, pan-TEAD ligands would generally control upstream Hippo pathway dysregulation.

Finally, Astra-Zeneca and academic laboratories reported TEAD ligands able to activate transcriptional activity of TEAD which could find interest in the field of regenerative medicine (cardiac regeneration, wound healing) [START_REF] Dey | Targeting the Hippo Pathway in Cancer, Fibrosis, Wound Healing and Regenerative Medicine[END_REF] and neurodegenerative diseases. [START_REF] Sahu | The Emerging Role of Hippo Signaling in Neurodegeneration[END_REF] Sustained YAP/TAZ activation can induce tumor formation in cells that are facing different environmental stresses, such as inflammation, or that already have pre-malignant oncogenic mutations thus increasing the risk of malignant transformation. However, the tissue overgrowth and tumor formation resulting from transient activation of YAP are often reversible upon cessation of YAP activation. [START_REF] Camargo | YAP1 increases organ size and expands undifferentiated progenitor cells[END_REF][START_REF] Dong | Elucidation of a universal size-control mechanism in Drosophila and mammals[END_REF] Thus, although the activation of YAP/TAZ can trigger undesired side effects, there might be a therapeutic window of YAP/TAZ activation that can be used to induce organ regeneration or wound healing. Combination of transcriptomics, gain-and loss-of-function studies, and functional genomics led to the identification of RB1, an unanticipated tumor suppressor role for YAP and TAZ in many cancers and stratification into binary superclassesbased on opposite pro-or anti-oncogenic activity of YAP/TAZ. [START_REF] Pearson | Binary pan-cancer classes with distinct vulnerabilities defined by pro-or anti-cancer YAP/TEAD activity[END_REF] The YAP/TAZ-negative class consisted of blood cancers, many neural cancers and welldifferentiated neuroendocrine cancers from many tissues, including lung, prostate, breast and the gastrointestinal tract whereas the YAP/TAZ-positive class consisted of solid cancers (adenocarcinoma, sarcoma, squamous cell cancers). [START_REF] Pearson | Simplifying cancer: binary pan-cancer superclasses stratified by opposite YAP/TEAD effects[END_REF] In this new partition, molecules which activate transcriptional activity found particular interest in certain cancers such as ER + breast cancer leading to the identification by Vivace Therapeutics of new Lats1/2 inhibitor. [START_REF] Ma | Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER + breast cancer[END_REF] With three molecules in phase 1 clinical trials, we are still far from a new anti-cancer drug available but knowledge of the biology of the Hippo pathway and downstream proteins YAP, TAZ and TEAD area is advancing by leaps and bounds. Knowledge on the structural interactions between TEAD1-4 and its different partners including YAP, TAZ and VGLL1-4 are still fragmented and new available data from Alphafold2 (https://alphafold.ebi.ac.uk/) [START_REF] Jumper | Highly Accurate Protein Structure Prediction with AlphaFold[END_REF] will lead to a better understanding of the complex network governing activation or inhibition of transcriptional activity of TEAD1-4. [START_REF] Liberelle | Toward the design of selective ligands of TEADs C-terminal domain[END_REF] Selective ligands of each TEAD member should be at least of interest for a better understanding on the redundancy or complementarity of TEAD members [START_REF] Li | TEAD1 and TEAD3 Play Redundant Roles in the Regulation of Human Epidermal Proliferation[END_REF][START_REF] Zhang | TEA Domain Transcription Factor 4 Is the Major Mediator of Yes-Associated Protein Oncogenic Activity in Mouse and Human Hepatoblastoma[END_REF] but also for precision medicine.

In the future, YAP/TAZ-TEAD interaction inhibitors will probably find limited interest as monotherapy since the Hippo pathway is not considered as a major dysregulation pathway in cancers, but more likely in combination with other new therapeutic modalities (KRAS, mTOR, NOTCH pathways) or with the current chemotherapy to avoid/limit chemoresistance [START_REF] Corvaisier | Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse[END_REF][START_REF] Zhao | YAP-induced resistance of cancer cells to antitubulin drugs is modulated by a hippo-independent pathway[END_REF][START_REF] Gujral | Hippo pathway mediates resistance to cytotoxic drugs[END_REF].

The new concept of binary pan-cancer classes will trigger greater interest for molecules that activate YAP/TAZ-TEAD interaction in addition to neurodegenerative disease, regenerative medicine and wound healing therapies and no doubt that in the future several patents will be deposited with this applications.

Figure 2 :

 2 Figure 2: (A): The 3D-structure model built by superimposition of hYAP250-171-hTEAD1209-426 complex (PDB code 3KYS) and hTEAD2217-447 (PDB code 5EMV) with interface 1 (hot pink), 2 (plum) and 3 (light green) and palmitate (light blue); (B): The three predicted druggable sites of TEAD (interface 2 (plum), interface 3 (light green) and internal pocket (light blue). Structural figures were generated with Chimera 1.14 (UCSF) [18].

[ 29 ]Figure 3 : 58 2. 1 . 2 .

 2935812 Figure 3: Structure of MGH-CP-1 , CP-55 and CP-58 2.1.2. Dana Farber Cancer Institute

Figure 4 :

 4 Figure 4: Structure of MYF-01-037, I-14 and I-29

Figure 5 :

 5 Figure 5: Structure of I-A-02, II-1, A-21 and A-16 2.1.3. Indianapolis University

Figure 6 :

 6 Figure 6: Structure of TED-347 and general structures of patent WO2020087063A1 2.2. Biotech companies 2.2.1. Inventiva

22 )Figure 7 :

 227 Figure 7: General structures of patents WO2017064277A1, WO2018185266A1 and WO2020070181A1 and some examples 2.2.2. Vivace Therapeutics KL Guan, one of the co-founder of Vivace Therapeutics, patented 2,7-disubstituted-9H-fluorene-9-one oxime in 2013. [40] CA3 inhibits the expression of YAP1 and therefore the transcriptional activity in esophageal adenocarcinoma cell lines and in xenograft mouse model in vivo.It acts also synergistically with 5-FU in inhibiting growth of esophageal adenocarcinoma in vivo.[START_REF] Song | A Novel YAP1 Inhibitor Targets CSC-Enriched Radiation-Resistant Cells and Exerts Strong Antitumor Activity in Esophageal Adenocarcinoma[END_REF] Extension of this patent on 2,7-disubstituted-9H-fluorene-9-one oxime was applied by Vivace Therapeutics in 2017.[START_REF] Therapeutics | Tricyclic compounds[END_REF] Since 2018, Vivace Therapeutics has deposited seven recent patent applications,[START_REF] Therapeutics | Non-Fused Tricyclic Compounds[END_REF][START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF][START_REF] Therapeutics | Benzocarbonyl Compounds[END_REF][46][START_REF] Therapeutics | Bicyclic compounds[END_REF][START_REF] Therapeutics | Bicyclic Compounds[END_REF][START_REF] Therapeutics | Heteroaryl compounds[END_REF] and their lead molecule VT-3989 enters in phase 1 clinical trial (NCT04665206) in early 2021 (https://clinicaltrials.gov/ct2/show/NCT04665206). It is evaluated in patients with metastatic solid tumors enriched for tumors with NF2 gene mutations. Two distinct families have been patented. The first one is inspired from the flufenamic acid structure[START_REF] Therapeutics | Non-Fused Tricyclic Compounds[END_REF][START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF][START_REF] Therapeutics | Benzocarbonyl Compounds[END_REF][46][START_REF] Therapeutics | Heteroaryl compounds[END_REF] and the biological data of VT-103[START_REF] Therapeutics | Benzosulfonyl Compounds[END_REF] (Figure8) have been detailed in a recent article.[START_REF] Tang | Small Molecule Inhibitors of TEAD Auto-Palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-Deficient Mesothelioma[END_REF] Thermal shift assay on the four TEAD family members suggested a selectivity of VT-103 for TEAD1, which was confirmed by a TEAD palmitoylation assay. VT-103 inhibits cell proliferation of a panel of NF2-deficient mesothelioma cell lines at low nanomolar IC50. VT-103 was evaluated in two malignant mesothelioma tumor xenograft mouse models with impressive outcomes, including an NCI-H226 model with TGI = 106% at 3 mg/kg p.o. and an NCI-

Figure 8 :

 8 Figure 8: Structures of main compounds described in ref 42.

Figure 9 :

 9 Figure 9: Structures of examples 37, 41 and 44.

Figure 10 :

 10 Figure 10: Structures of compounds 57B and 58.

Figure 11 :

 11 Figure 11: Structures of compounds 53, 54 and 55 from patent WO2021097110A1.[START_REF] Genentech | Therapeutic compounds and methods of use[END_REF]

Figure 15 :

 15 Figure 15: Structures of compounds 24, 43A and 70 from patent WO2021108483A1.[START_REF] Genentech | Therapeutic compounds[END_REF]

Figure 16 :

 16 Figure 16: Structures of compound 17 from patent WO2021178339. [57] 2.2.4. Ikena Oncology Ikena Oncology released patent WO2020243423A1 [58] presenting a series of around 500 examples, derived from the general structure presented in Figure 17.

Figure 17 :

 17 Figure 17: General structure of compounds from patent WO2020243423A1, [58] I-12 and I-186

Figure 19 :

 19 Figure 19: General structures of patented compounds [61] and structures of examples 144 and 147.

Figure 21 :

 21 Figure 21: General patented structures [65, 66] and example of one the most active compounds

Figure 22 :

 22 Figure 22: structures of Q2 and modified VGLL4 fragment (eicosapeptide 4E)

  [START_REF] Li | Structural Insights into the YAP and TEAD Complex[END_REF] and isomer 1 of I-186 were evaluated on NCI-H226 or MSTO211H xenograft mice. They both inhibited tumor growth without affected body weight and significantly decreased CTGF mRNA levels. The patented compounds presented interaction with hTEAD2 C-terminal domain as shown by TSA (thermal shift assay) with Tm ranging from 0.4 to 18 °C and inhibited luciferase activity in the MCF-7 TEAD reporter gene assay with IC50 between 39 nM and 6 µM. Example 2 (Figure18)(MCF-7 TEAD RGA IC50 = 41 nM, hTEAD2 Tm = 10.6 °C, no PK data reported) is active in vivo in a 62-day murine NCIH226 xenograft efficacy model by showing dose-dependent activity and tumor stasis at the highest dose of 250 mg/kg p.o..

	Figure 18: Structure of Example 2 [59]
	2.3. Big pharma
	2.3.1. Novartis
	Ikena Oncology declared IK-930 clinical trial phase I launch in early 2022 (NCT05228015),
	(https://clinicaltrials.gov/ct2/show/NCT05228015).
	2.2.5. Basilea Pharmaceutica

Basilea Pharmaceutica recently described in a patent application a series of 1,2,4-oxadiazol-5-one derivatives.

[START_REF] Basilea | 1,2,4-Oxadiazol-5-one Derivatives for the Treatment of Cancer[END_REF]

These molecules shared structural similarity with flufenamic acid, where the carboxylic acid group has been replaced with an 1,2,4-oxadiazol-5-one heterocycle.

Funding

This work was financially supported by the Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation, the University of Lille and INSERM.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Author contributions BZ and PC collected, analyzed and abstracted the patents. BZ, PM and PC wrote and revised the article.

ORCID

Benjamin Zagiel: 0000-0002-1047-5013 Patricia Melnyk: 0000-0002-9555-3446 Philippe Cotelle: 0000-0003-0924-0433