Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors

Sturbaut, Manon; Bailly, Fabrice; Coevoet, Mathilde; Sileo, Pasquale; Pugnière, Martine; Liberelle, Maxime; Magnez, Romain; Thuru, Xavier; Chartier-Harlin, Marie-Christine; Melnyk, Patricia; Gelin, Muriel; Allemand, Frédéric; Guichou, Jean-François; Cotelle, Philippe

doi:10.1016/j.ejmech.2021.113835

Cited by 29 publications

(26 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Around 70 of them, including compound 1, produced chemical shift changes indicative of binding in the protein spectra. Then, 2D [ 13 C, 1 H]À HMQC spectra of uniformly 13 C, 15 N-labeled TEAD4(217-434) in the presence of these compounds were measured for confirmation of binding. In these experiments the binding of 1 to TEAD4 was clearly established.…”

Section: Search For Hits By High Throughput In Silico Dockingmentioning

confidence: 99%

“…Although showing very weak activity, 2 was considered as an attractive starting point for our YAP-TEAD medicinal chemistry efforts. The molecule was small and occupying only partially the Ω-loop pocket, it offered possibilities of creating additional productive interactions with the pocket to improve , 1 H]À HMQC spectra of uniformly 13 C, 15 N-labeled TEAD4(217-434) at a concentration of 30 μM in the absence (black) and in the presence of compound 1 at increasing concentrations (red, 30 μM; blue, 60 μM; green, 120 μM; grey, 240 μM). Bottom: chemical shift changes (Δδ) for the 13 CH 3 resonance enclosed in the blue box of the upper panel as a function of compound 1 concentration.…”

Section: Search For Hits By High Throughput In Silico Dockingmentioning

confidence: 99%

“…A few attempts to directly target the YAP-TEAD protein-protein interaction with small non peptide molecules are reported in the literature. [13][14][15][16] In all cases, only molecules with weak activity were identified.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition

et al. 2022

View full text Add to dashboard Cite

Inhibition of the YAP‐TEAD protein‐protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug‐like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP‐TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure‐based design.

show abstract

Section: Search For Hits By High Throughput In Silico Dockingmentioning

confidence: 99%

Section: Search For Hits By High Throughput In Silico Dockingmentioning

confidence: 99%

See 1 more Smart Citation

The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Tri-substituted pyrazoles are small molecule ligands that bind TEAD interface 2 and can be improved to act as effective YAP-TEAD disruptors [ 47 ]. At the interface 3 site, a small molecule ligand with a dioxo-benzoisothiazole scaffold has been reported to act as a canonical disruptor of YAP-TEAD interaction [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex

et al. 2022

View full text Add to dashboard Cite

Disrupting the formation of the oncogenic YAP/TAZ-TEAD transcriptional complex holds substantial therapeutic potential. However, the three protein interaction interfaces of this complex cannot be easily disrupted using small molecules. Here, we report that the pharmacologically active small molecule aurintricarboxylic acid (ATA) acts as a disruptor of the TAZ-TEAD complex. ATA was identified in a high-throughput screen using a TAZ-TEAD AlphaLISA assay that was tailored to identify disruptors of this transcriptional complex. We further used fluorescence polarization assays both to confirm disruption of the TAZ-TEAD complex and to demonstrate that ATA binds to interface 3. We have previously shown that cell-based models that express the oncogenic TAZ-CAMTA1 (TC) fusion protein display enhanced TEAD transcriptional activity because TC functions as an activated form of TAZ. Utilizing cell-based studies and our TC model system, we performed TC/TEAD reporter, RNA-Seq, and qPCR assays and found that ATA inhibits TC/TEAD transcriptional activity. Further, disruption of TC/TEAD and TAZ/TEAD interaction by ATA abrogated anchorage-independent growth, the phenotype most closely linked to dysregulated TAZ/TEAD activity. Therefore, this study demonstrates that ATA is a novel small molecule that has the ability to disrupt the undruggable TAZ-TEAD interface.

show abstract

“…Transcriptional enhanced associate domain (TEAD) family take vital effects in the organism [7]. The TEAD family contains four members (TEAD1, TEAD2, TEAD3 and TEAD4), which each have tissue-specific roles, including trophectoderm, cardiogenesis, lineage determination and neural development [8]. TEAD family is regarded to be primarily combine to the DNA and it is also the downstream nuclear effectors of the Hippo pathway [9].…”

Section: Introductionmentioning

confidence: 99%

Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

Ren

Wang

Yan

et al. 2022

Aging

View full text Add to dashboard Cite

Objective: Transcriptional enhanced associate domain (TEAD) family consists of four members TEAD1/2/3/4 that regulate cell growth, stem cell functions and organ development. As the downstream of Hippo signaling pathway, TEAD family is involved in the progression of several cancers. However, the precise biology functions of TEAD family in hepatocellular carcinoma (HCC) have not been reported yet. Methods: We apply bioinformatics analysis based on databases including UALCAN, Oncomine, GEPIA, Kaplan-Meier plotter, WebGestalt, cBioPortal, TIMER2.0, and in vitro experimental evidence to identify the exact roles of TEAD family in HCC. Results: The results indicated that TEAD2/4 were significantly upregulated in HCC compared with normal tissues. Downregulated of TEAD2 could promote the death of HCC cells through inducing ferroptosis by iron accumulation and subsequent oxidative damage. According to the Kaplan-Meier plotter database, we found that the high expression of TEAD2 was significantly associated with poor disease-specific survival, overall survival, progression-free survival and relapse-free survival. In aspect of cancer immunity, Tumor Immune Estimation Resource algorithm showed that the expression of TEAD family members was obviously related to multiple of infiltrating immune cells including macrophages, neutrophils, dendritic cells, B cells, CD8+ T cells and CD4+ T cells. Finally, we conducted the functional enrichment analysis including protein-protein interaction

show abstract

Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors

Cited by 29 publications

References 47 publications

The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition

The First Class of Small Molecules Potently Disrupting the YAP‐TEAD Interaction by Direct Competition

Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex

Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

Contact Info

Product

Resources

About