Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration

被引：8

作者：

Fnaiche, Ahmed ^{[1
]}

Chan, Hwai-Chien ^{[1
]}

Paquin, Alexis ^{[1
]}

Suarez, Narjara Gonzalez ^{[1
]}

Vu, Victoria ^{[2
]}

Li, Fengling ^{[2
]}

Allali-Hassani, Abdellah ^{[2
,3
]}

Cao, Michelle Ada ^{[2
,5
]}

Szewczyk, Magdalena M. ^{[2
]}

Bolotokova, Albina ^{[2
]}

Allemand, Frederic ^{[4
]}

Gelin, Muriel ^{[4
]}

Barsyte-Lovejoy, Dalia ^{[2
]}

Santhakumar, Vijayaratnam ^{[2
]}

Vedadi, Masoud ^{[5
,6
]}

Guichou, Jean-Francois ^{[4
]}

Annabi, Borhane ^{[1
]}

Gagnon, Alexandre ^{[1
]}

机构：

[1] Univ Quebec Montreal, Univ Quebec a Montreal, Montreal, PQ H3C 3P8, Canada

[2] Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[3] Incyte Corp, Incyte Res Inst, 1801 Augustine Cut, Wilmington, DE 19803 USA

[4] Univ Montpellier, Ctr Biol Struct, INSERM, CNRS, F-34090 Montpellier, France

[5] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[6] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3, Canada

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年 / 14卷 / 12期

基金：

加拿大自然科学与工程研究理事会;

关键词：

YAP-TEAD; Hippo pathway; Transcription factors; Flufenamic acid; Covalent inhibitors; HIPPO PATHWAY; STRUCTURAL INSIGHTS; YAP; YAP/TAZ; PALMITOYLATION; HOMEOSTASIS; DESIGN; POCKET; ROLES;

D O I：

10.1021/acsmedchemlett.3c00386

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 CTGF, CYR61, AXL, and NF2 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.

引用

页码：1746 / 1753

页数：8

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