| Added by | alainmange |
|---|---|
| Group name | PlateformePP2I |
| Item Type | Journal Article |
| Title | Discovery of a cryptic site at the interface 2 of TEAD - Towards a new family of YAP/TAZ-TEAD inhibitors |
| Creator | Sturbaut et al. |
| Author | Manon Sturbaut |
| Author | Fabrice Bailly |
| Author | Mathilde Coevoet |
| Author | Pasquale Sileo |
| Author | Maxime Liberelle |
| Author | Romain Magnez |
| Author | Xavier Thuru |
| Author | Marie-Christine Chartier-Harlin |
| Author | Patricia Melnyk |
| Author | Muriel Gelin |
| Author | Jean-François Guichou |
| Author | Philippe Cotelle |
| Abstract | 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. |
| Publication | European Journal of Medicinal Chemistry |
| Volume | 226 |
| Pages | 113835 |
| Date | 2021-09-06 |
| Journal Abbr | Eur J Med Chem |
| Language | eng |
| DOI | 10.1016/j.ejmech.2021.113835 |
| ISSN | 1768-3254 |
| Library Catalog | PubMed |
| Extra | PMID: 34509860 |
| Tags | author, Binding assays, Hippo pathway, Interface 2, original, pp2i, TEAD cryptic binding pocket, TEAD inhibition |
| Date Added | 2021/09/22 - 17:59:08 |
| Date Modified | 2021/10/11 - 11:41:04 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
