6S60

Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor

Summary for 6S60

• Entry DOI: 10.2210/pdb6s60/pdb
• Descriptor: Transcriptional enhancer factor TEF-4, MYRISTIC ACID, 4-[3-(3,4-dichlorophenyl)-4-[(phenylmethyl)carbamoyl]pyrazol-1-yl]butanoic acid, ... (4 entities in total)
• Functional Keywords: tead2, inhibitor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 55867.23

Authors

Sturbaut, M.,Allemand, F.,Guichou, J.F. (deposition date: 2019-07-02, release date: 2020-07-22, Last modification date: 2024-11-13)

Primary citation

Sturbaut, M.,Bailly, F.,Coevoet, M.,Sileo, P.,Pugniere, M.,Liberelle, M.,Magnez, R.,Thuru, X.,Chartier-Harlin, M.C.,Melnyk, P.,Gelin, M.,Allemand, F.,Guichou, J.F.,Cotelle, P.
Discovery of a cryptic site at the interface 2 of TEAD - Towards a new family of YAP/TAZ-TEAD inhibitors.
Eur.J.Med.Chem., 226:113835-113835, 2021

PubMed 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.

PubMed: 34509860
DOI: 10.1016/j.ejmech.2021.113835

Experimental method

X-RAY DIFFRACTION (2 Å)