Selective Small-Chemical Inhibitors of Protein Arginine Methyltransferase 5 with Anti-Lung Cancer Activity
Kong, Gui-Mei, Yangzhou University Yu, Min, Yunnan University Gu, Zhongping, Fourth Military Medical University, China Chen, Zhi, Chinese Academy of Sciences Xu, Rui-Ming, Chinese Academy of Sciences O'Bryant, Deon, Clark Atlanta University Wang, Zhengxin, Clark Atlanta University
2017-08-14
2010-2019
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50values ranging from 0.1 to 6 ?M. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.
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articles
PLOS One
Clark Atlanta University
10.1371/journal.pone.0181601
http://hdl.handle.net/20.500.12322/cau.ir:2017_wang
http://rightsstatements.org/vocab/InC/1.0/