Academic Journal
Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors
| العنوان: | Discovery of a cryptic site at the interface 2 of TEAD – Towards a new family of YAP/TAZ-TEAD inhibitors |
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| المؤلفون: | Sturbaut, Manon, Bailly, Fabrice, Coevoet, Mathilde, Sileo, Pasquale, Pugniere, Martine, Liberelle, Maxime, Magnez, Romain, Thuru, Xavier, Chartier-Harlin, Marie-Christine, Melnyk, Patricia, Gelin, Muriel, Allemand, Frédéric, Guichou, Jean-François, Cotelle, Philippe |
| المساهمون: | Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU 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), Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Pasteur Network (Réseau International des Instituts Pasteur)-Pasteur Network (Réseau International des Instituts Pasteur)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale Montpellier (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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) |
| المصدر: | ISSN: 0223-5234. |
| بيانات النشر: | CCSD Elsevier |
| سنة النشر: | 2021 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | TEAD inhibition, TEAD cryptic binding pocket, Interface 2, Binding assays, Hippo pathway, [CHIM]Chemical Sciences |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/34509860; PUBMED: 34509860 |
| DOI: | 10.1016/j.ejmech.2021.113835 |
| الاتاحة: | https://hal.science/hal-03429462 https://hal.science/hal-03429462v1/document https://hal.science/hal-03429462v1/file/S022352342100684X.pdf https://doi.org/10.1016/j.ejmech.2021.113835 |
| Rights: | http://creativecommons.org/licenses/by-nc/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.3B12031B |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ejmech.2021.113835 |
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