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

• Published in: Frontiers in chemistry 2022-06, Vol.10, p.888727-888727
• Main Authors: Wang, Caijiao, Dong, Luyao, Zhao, Ziqi, Zhang, Zeqing, Sun, Yutong, Li, Chonglong, Li, Guoqing, You, Xuefu, Yang, Xinyi, Wang, Hao, Hong, Wei
• Format: Article
• Language: English
• Subjects: Chemistry; EMT; inhibitors; molecular docking; PRMT; TGF-β
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2022.888727

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 (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-β1-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.