8PUY

TEAD2 with a covalent inhibitor

8PUY の概要

• エントリーDOI: 10.2210/pdb8puy/pdb
• 関連するPDBエントリー: 8PUX
• 分子名称: Transcriptional enhancer factor TEF-4, ~{N}-[3-[(3-pentoxyphenyl)amino]phenyl]propanamide, MYRISTIC ACID, ... (4 entities in total)
• 機能のキーワード: tead2, inhibitor, covalent, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55533.00

構造登録者

Guichou, J.F.,Gelin, M.,Allemand, F. (登録日: 2023-07-17, 公開日: 2023-12-13, 最終更新日: 2024-11-06)

主引用文献

Fnaiche, A.,Chan, H.C.,Paquin, A.,Gonzalez Suarez, N.,Vu, V.,Li, F.,Allali-Hassani, A.,Cao, M.A.,Szewczyk, M.M.,Bolotokova, A.,Allemand, F.,Gelin, M.,Barsyte-Lovejoy, D.,Santhakumar, V.,Vedadi, M.,Guichou, J.F.,Annabi, B.,Gagnon, A.
Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration.
Acs Med.Chem.Lett., 14:1746-1753, 2023

PubMed Abstract: The transcription factor YAP-TEAD is the downstream effector of the Hippo pathway which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation of the Hippo pathway has been correlated with carcinogenic processes. A co-crystal structure of TEAD with its endogenous ligand palmitic acid (PA) as well as with flufenamic acid (FA) has been disclosed. Here we report the development of HC-258, which derives from FA and possesses an oxopentyl chain that mimics a molecule of PA as well as an acrylamide that reacts covalently with TEAD's cysteine. HC-258 reduces the , , , and transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine.

PubMed: 38116405
DOI: 10.1021/acsmedchemlett.3c00386

実験手法

X-RAY DIFFRACTION (2.2 Å)