title: Discovery and optimization of selective inhibitors of protein arginine methyltransferase 5 by docking-based virtual screening.
abstract: Protein arginine methyltransferase 5 (PRMT5) is a type II PRMT enzyme critical for diverse cellular processes and different types of cancers. Many efforts have been made to discover novel scaffold PRMT5 inhibitors. Herein, we report the discovery of DC_P33 as a hit compound of PRMT5 inhibitor, identified by molecular docking based virtual screening and3H-labeled radioactive methylation assays. Structure-activity relationship (SAR) analysis was performed on the analogs of DC_P33 and then structural modifications were done to improve its activity. Among the derivatives, the compound DC_C01 displayed an IC50value of 2.8 μM, and good selectivity toward PRMT1, EZH2 and DNMT3A. Moreover, DC_C01 exhibited anti-proliferation activities against Z-138, Maver-1, and Jeko-1 cancer cells with EC50values of 12 μM, 12 μM, and 10.5 μM, respectively. Taken together, these results contribute to the development of specific inhibitors against PRMT5 and cancer therapy.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. myzheng@simm.ac.cn cluo@simm.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.forename: Bidong
authors.initials: B
authors.lastname: Zhang
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Mao
authors.forename: Chenhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Xing
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Mingyue
authors.initials: M
authors.lastname: Zheng
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases