Monday, December 4, 2023

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

Ahmed Fnaiche, Hwai-Chien Chan, Alexis Paquin, Narjara González Suárez, Victoria Vu, Fengling Li, Abdellah Allali-Hassani, Michelle Ada Cao, Magdalena M. Szewczyk, Albina Bolotokova, Frédéric Allemand, Muriel Gelin, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Masoud Vedadi, Jean-François Guichou, Borhane Annabi, and Alexandre Gagnon
ACS Medicinal Chemistry Letters 2023

DOI: 10.1021/acsmedchemlett.3c00386

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.



Rapid, potent, and persistent covalent chemical probes to deconvolute PI3Kα signaling

Lukas Bissegger,  Theodora A. Constantin,  Erhan Keles,  Luka Raguž,   Isobel Barlow-Busch,  Clara Orbegozo,   Thorsten Schaefer,  Valentina...