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

Caijiao Wang; Luyao Dong; Ziqi Zhao; Zeqing Zhang; Yutong Sun; Chonglong Li; Guoqing Li; Xuefu You; Xinyi Yang; Hao Wang; Wei Hong

doi:10.3389/fchem.2022.888727

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

Front Chem. 2022 Jun 8:10:888727. doi: 10.3389/fchem.2022.888727. eCollection 2022.

Authors

Caijiao Wang¹, Luyao Dong², Ziqi Zhao³, Zeqing Zhang¹, Yutong Sun⁴, Chonglong Li¹, Guoqing Li², Xuefu You², Xinyi Yang², Hao Wang^{3

5

6}, Wei Hong^{1

7}

Affiliations

¹ School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan, China.
² Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ School of Pharmacy, Minzu University of China, Beijing, China.
⁴ School of Pharmacy, Ningxia Medical University, Yinchuan, China.
⁵ Key Laboratory of Ethnomedicine, Minzu University of China, Ministry of Education, Beijing, China.
⁶ Institute of National Security, Minzu University of China, Beijing, China.
⁷ Jingjinji National Center of Technology Innovation, Beijing, China.

Abstract

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-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.

Keywords: EMT; PRMT; TGF-β; inhibitors; molecular docking.