Xinpeng Liu, Yaxuan Gao, Jianxin Yang, Zhuoxin Fu, Weina Yang, Jiankang Sun, Yufei Wang, Ruofei Huang, Runan Zheng, Qinglong Xu, Haoliang Yuan, Liang Dai, Zhiqi Feng
Hepatic fibrosis is a common consequence of chronic liver diseases, yet current therapeutic options remain limited. The transcriptional enhanced associate domain (TEAD) serves as a nuclear-binding partner of YAP/TAZ, and the YAP/TAZ-TEAD complex is a critical driver of hepatic stellate cell (HSC) activation and fibrogenesis. In this study, we designed and synthesized a series of indole derivatives as novel TEAD inhibitors. Compound 8 exhibited appreciable TEAD inhibitory activity, a pan-TEAD inhibitory profile, and direct binding to TEAD. Moreover, compound 8 dose-dependently suppressed the expression of representative YAP/TAZ-TEAD target genes. Notably, compound 8 exhibited good anti-hepatic fibrotic effects both in vitro and in vivo. Collectively, compound 8 provides a promising lead for the development of TEAD-targeted anti-hepatic fibrotic agents.