1. Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors
- Author
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Jean-François Guichou, Manon Sturbaut, Romain Magnez, Marie-Christine Chartier-Harlin, Patricia Melnyk, Martine Pugnière, Maxime Liberelle, Pasquale Sileo, Philippe Cotelle, Xavier Thuru, Muriel Gelin, Fabrice Bailly, Mathilde Coevoet, Frédéric Allemand, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centrale Lille, This work was financially supported by grants from le Ministère de l’Education et de la Recherche and the University of Lille (M. S. and P.S.) and fundings from le Cancéropôle Nord-Ouest (Mobility Support Program for Young Researchers, M. S.). This work was also supported by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Lille Neurosciences & Cognition - U 1172 (LilNCog), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Models, Molecular ,TEAD cryptic binding pocket ,Hippo pathway ,Antineoplastic Agents ,Cell Cycle Proteins ,Ligands ,TEAD inhibition ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Transcription (biology) ,Drug Discovery ,Humans ,[CHIM]Chemical Sciences ,Tissue homeostasis ,Binding assays ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,0303 health sciences ,Hippo signaling pathway ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cell growth ,Organic Chemistry ,HEK 293 cells ,TEA Domain Transcription Factors ,General Medicine ,Interface 2 ,3. Good health ,Cell biology ,HEK293 Cells ,030220 oncology & carcinogenesis ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Phosphorylation ,Pyrazoles ,Nuclear transport ,Cellular model ,Drug Screening Assays, Antitumor ,Transcription Factors - Abstract
International audience; The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.
- Published
- 2021
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