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

Area of Science:

• Molecular Biology
• Biochemistry
• Cancer Research

Background:

• The YAP-TEAD transcription factor is a key regulator of the Hippo pathway, influencing cell growth and tissue repair.
• Hippo pathway dysregulation is linked to various cancers, highlighting its role in carcinogenesis.
• Previous studies revealed TEAD structures bound to palmitic acid (PA) and flufenamic acid (FA).

Purpose of the Study:

• To develop a novel inhibitor targeting the YAP-TEAD complex.
• To investigate the inhibitory effects of the new compound on cancer cell behavior and gene expression.

Main Methods:

• Development of HC-258, a flufenamic acid derivative with a PA-mimicking chain and a reactive acrylamide group.
• Assessing HC-258's impact on CTGF, CYR61, AXL, and NF2 transcript levels.
• Evaluating HC-258's effect on MDA-MB-231 breast cancer cell migration.
• Co-crystallization of HC-258 with human TEAD2 (hTEAD2) to determine its binding mode.

Main Results:

• HC-258 was successfully developed, incorporating structural features to interact with TEAD.
• HC-258 significantly reduced the transcript levels of CTGF, CYR61, AXL, and NF2.
• The compound effectively inhibited the migration of MDA-MB-231 breast cancer cells.
• Co-crystallization confirmed HC-258 binds to the PA pocket of hTEAD2 and forms a covalent bond with cysteine.

Conclusions:

• HC-258 is a potent inhibitor of YAP-TEAD transcriptional activity.
• The compound demonstrates anti-migratory effects in breast cancer cells.
• HC-258's mechanism involves covalent binding within the TEAD PA pocket, presenting a promising therapeutic lead.