期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 14, 页码 6289-6304出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00587
关键词
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资金
- Chinese Academy of Sciences [XDA12020304]
- Ministry of Science and Technology of China [2015CB910304]
- National Natural Science Foundation of China [21472208, 81625022, 81430084, 21210003, 81230076]
- Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]
- Shandong Talents Team Cultivation Plan of University Preponderant Discipline [10027]
- China Postdoctoral Science Foundation [2016M601676]
- Shanghai Sailing Program [17YF1423100]
PRMT5 plays important roles in diverse cellular processes and is upregulated in several hutnan malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 mu M) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding, of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a K-d of 0.987 mu M. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.
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