Discovery of Selective Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors and Biological Evaluations
PRMT5 is an important protein arginine methyltransferase that catalyzes the symmetric dimethylation of arginine resides on histones or non-histone substrate proteins.It has been thought as a promising target for many diseases,particularly cancer.Despite the potential applications of PRMT5 inhibitors in cancer treatment,very few of PRMT5i have been publicly reported.In this investigation,virtual screening and structure-activity relationship(SAR)studies were carried out to discovery novel PRMT5i,which finally led to the identification of a number of new PRMT5i.The most active compound,P5i-6,exhibited a considerable inhibitory potency against PRMT5 with an IC50 value of 0.57μM,and a high selectivity for PRMT5 against other tested PRMTs.It displayed a very good anti-viability activity against two colorectal cancer cell lines,HT-29 and DLD-1,and one hepatic cancer cell line,HepG2,in a sensitivity assay against 36 different cancer cell lines.Western Blot assays indicated that P5i-6 selectively inhibited the symmetric dimethylations of H4R3 and H3R8 in DLD-1 cells.Overall,P5i-6 could be used as a chemical probe to investigate new functions of PRMT5 in biology and also served as a good lead compound for the development of new PRMT5-targeting therapeutic agents.
Sen Ji Shuang Ma Wen-Jing Wang Shen-Zhen Huang Tian-qi Wang Rong Xiang Yi-Guo Hu Qiang Chen Lin-Li Li Sheng-Yong Yang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy,West China Hospital Department of Clinical Medicine,School of Medicine,Nankai University,Tianjin,300071,China West China School of Pharmacy,Sichuan University,Sichuan,China
国内会议
第九届国际分子模拟与信息技术应用学术会议(ICMS&I2018)
太原
英文
247-283
2018-05-01（万方平台首次上网日期，不代表论文的发表时间）