A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH- driven HCC in mice

Abstract Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we reported the discovery of 753b, a BCL-xL proteolysis targeting chimera (PROTAC), as a potent and liver-tropic senolytic. We found that 753b can selectively clear senescent hepatocytes in aged mice and the STAM mice even though it can potently kill various SnCs in vitro. This is in part because 753b is enriched in the liver after its administration by ip injection. Moreover, 753b treatment can effectively reduce the development of non-alcoholic steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (HCC) in the STAM mice. These findings suggest that 753b has the potential to be developed as a novel therapeutic for NAFLD and NASH-driven HCC. Citation Format: Yang Yang, Natacha Jn-Simon, Wanyi Hu, Peiyi Zhang, Guangrong Zheng, Liya Pi, Yonghan He, Daohong Zhou. A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B009.