title: Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.
abstract: Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 μM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 μM, 13.1 μM and 11.4 μM, respectively.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Xu-Ri
authors.initials: XR
authors.lastname: Yu
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Xiao-Ai
authors.initials: XA
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China.
authors.forename: Zheng-Yan
authors.initials: ZY
authors.lastname: Fu
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015394:Molecular Structure; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001562:Benzimidazoles; D009574:Nitro Compounds; D011743:Pyrimidines; D011484:Protein-Arginine N-Methyltransferases
keywords: Epigenetics; PRMT1; Protein arginine methyltransferase; Small molecule inhibitor; Structure–activity relationship