Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell

Protein arginine methyltransferase 1 (PRMT1) can catalyze the protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes including epithelial-mesenchymal transition (EMT) and EMT-mediated mobility of cancer cells. The upregulation of PRMT1 is involved in a diverse range of cancer, such as lung cancer, and there is an urgent need to develop novel and potent PRMT1 inhibitors. In this article, a series of 2,5-substituted furan derivatives and 2,4-substituted thiazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and 10 compounds demonstrated significant inhibitory effects against PRMT1. Among them, the most potent inhibitor, compound 1r (WCJ-394), significantly affected the expression of PRMT1-related proteins in A549 cells and downregulated the expression of mesenchymal markers, by which WCJ-394 inhibited the TGF-beta 1-induced EMT in A549 cells and prevented the cancer cell migration. The current study demonstrated that WCJ-394 was a potent PRMT1 inhibitor, which could be used as the leading compound for further drug discovery.

Automated summary

Protein arginine methyltransferase 1 (PRMT1) is an enzyme that catalyzes protein arginine methylation and is involved in various biological processes such as EMT and cancer cell migration. This study designed and synthesized a series of compounds targeting the substrate binding site of PRMT1, and identified compound 1r (WCJ-394) as the most potent inhibitor. WCJ-394 affected the expression of PRMT1-related proteins and inhibited TGF-beta 1-induced EMT and cancer cell migration.