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

作者：Chen Zhou, Chunbao Sun, Wei Zhou, Tian Tian, Daniel Schultz, Tong Wu, Mu Yu, Lizi Wu, Liya Pi, Chenglong Li · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00925 · 被引用次数：10 · 研究领域：Hippo pathway signaling and YAP/TAZ、Ubiquitin and proteasome pathways、Lipid metabolism and biosynthesis

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.