Development\nof Novel Indole-Based Covalent Inhibitors\nof TEAD as Potential Antiliver Cancer Agents

Abnormal activation of the YAP transcriptional signaling\npathway\ndrives proliferation in many hepatocellular carcinoma (HCC) and hepatoblastoma\n(HB) cases. Current treatment options often face resistance and toxicity,\nhighlighting the need for alternative therapies. This article reports\nthe discovery of a hit compound <b>C-3</b> from docking-based\nvirtual screening targeting TEAD lipid binding pocket, which inhibited\nTEAD-mediated transcription. Optimization led to the identification\nof a potent and covalent inhibitor <b>CV-4-26</b> that exhibited\ngreat antitumor activity in HCC and HB cell lines in vitro, xenografted\nhuman HCC, and murine HB in vivo. These outcomes signify the potential\nof a highly promising therapeutic candidate for addressing a subset\nof HCC and HB cancers. In the cases of current treatment challenges\ndue to high upregulation of YAP-TEAD activity, these findings offer\na targeted alternative for more effective interventions against liver\ncancer.