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

• Published in: Journal of medicinal chemistry Vol. 66; no. 12; pp. 7969 - 7987
• Main Authors: Bao, Yunyang, Niu, Tianyu, Zhu, Jingyang, Mei, Yuheng, Shi, Yulong, Meng, Runze, Duan, Qionglu, Zhang, Na, Fan, Tianyun, Wang, Yanxiang, Pang, Yudong, Li, Yinghong, He, Hongwei, Song, Danqing
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.06.2023; Amer Chemical Soc
• Subjects: Animals; Antifibrotic Agents; Chemistry, Medicinal; Fibrosis; Life Sciences & Biomedicine; Liver; Liver Cirrhosis - pathology; Matrines; Mice; Pharmacology & Pharmacy; Rats; RNA-Binding Protein EWS; Sarcoma, Ewing - pathology; Science & Technology; STELLATE CELLS; ACTIVATION; PROTEIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00286

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.