Development of HC-258, a Covalent Acrylamide TEAD Inhibitor That Reduces Gene Expression and Cell Migration
The transcription factor YAP-TEAD may be the downstream effector from the Hippo path which controls cell proliferation, apoptosis, tissue repair, and organ growth. Dysregulation from the Hippo path continues to be correlated with cancer causing processes. A co-very structure of TEAD using its endogenous ligand palmitic acidity (PA) in addition to with flufenamic acidity (FA) continues to be disclosed. Ideas report the introduction of HC-258, which stems from FA and offers an oxopentyl chain that mimics a molecule of PA plus an acrylamide that reacts covalently with TEAD’s cysteine. HC-258 cuts down on the CTGF, CYR61, AXL, and NF2 transcript levels and inhibits the migration of MDA-MB-231 cancer of the breast cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD’s PA pocket, where it forms a covalent bond using its cysteine.