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

Abnormal activation of the YAP transcriptional signaling
pathway
drives proliferation in many hepatocellular carcinoma (HCC) and hepatoblastoma
(HB) cases. Current treatment options often face resistance and toxicity,
highlighting the need for alternative therapies. This article reports
the discovery of a hit compound C-3 from docking-based
virtual screening targeting TEAD lipid binding pocket, which inhibited
TEAD-mediated transcription. Optimization led to the identification
of a potent and covalent inhibitor CV-4-26 that exhibited
great antitumor activity in HCC and HB cell lines in vitro, xenografted
human HCC, and murine HB in vivo. These outcomes signify the potential
of a highly promising therapeutic candidate for addressing a subset
of HCC and HB cancers. In the cases of current treatment challenges
due to high upregulation of YAP-TEAD activity, these findings offer
a targeted alternative for more effective interventions against liver
cancer.