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

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