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

A series of new tricyclic matrinane derivatives werecontinuouslysynthesized and evaluated for their inhibitory effects on genes andproteins related to hepatic fibrosis at the cellular level, includingcollagen type I alpha 1 chain (COL1A1), alpha smooth muscle actin(alpha-SMA), connective tissue growth factor (CTGF), and matrixmetalloprotein 2 (MMP-2). Among them, compound 6k exertedan appealing potency and significantly reduced liver injury and fibrosisin both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-basedprotein profiling (ABPP) assay indicated that 6k mightdirectly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibitits function and affect the expression of downstream liver fibrosis-relatedgenes and thus regulate liver fibrosis. These results provided a potentialnovel target for the treatment of liver fibrosis and powerful informationfor the development of tricyclic matrinanes into promising anti-hepaticfibrosis agents.

Automated summary

A series of new tricyclic matrinane derivatives were synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis. Compound 6k showed strong activity and significantly reduced liver injury and fibrosis in both BDL rats and Mdr2 knockout mice. The ABPP assay indicated that 6k might directly bind to EWSR1 to inhibit its function and affect downstream liver fibrosis-related genes expression, providing a potential novel target for the treatment of liver fibrosis.