Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1)

  • J Med Chem. 2023 Jun 22;66(12):7969-7987. doi: 10.1021/acs.jmedchem.3c00286.
Yunyang Bao  1 ,  Tianyu Niu  1 ,  Jingyang Zhu  1 ,  Yuheng Mei  1 ,  Yulong Shi  1 ,  Runze Meng  1 ,  Qionglu Duan  1 ,  Na Zhang  1 ,  Tianyun Fan  1 ,  Yanxiang Wang  1 ,  Yudong Pang  1 ,  Yinghong Li  1 ,  Hongwei He  1 ,  Danqing Song  1
Affiliations
  • 1. Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China.
PMID: 37294950 DOI: 10.1021/acs.jmedchem.3c00286
Abstract

A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including Collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.

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