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Identification of Selective, Cell Active Inhibitors of Protein Arginine Methyltransferase 5 through Structure-Based Virtual Screening and Biological Assays
journal contribution
posted on 2018-04-19, 00:00 authored by Fei Ye, Weiyao Zhang, Xiaoqing Ye, Jia Jin, Zhengbing Lv, Cheng LuoProtein
arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme,
is reported as an important therapeutic target in leukemia and lymphoma.
In the present study, based on the combination of virtual screening
and biochemical validations, we discovered a series of small-molecule
inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most
potent activity with IC50 value of 1.7 μM and displayed
good selectivity against other methyltransferases. Further treatment
with DC_Y134 inhibited the proliferation of several hematological
malignancy cell lines by causing cell cycle arrest and apoptosis.
Western blot assays indicated that DC_Y134 reduced the cellular symmetrically
dimethylated levels. In addition, we analyzed the binding mode of
DC_Y134 through molecular docking, which revealed that DC_Y134 occupies
the binding site of substrate arginine and explained the selectivity
of this inhibitor. Taken together, compound DC_Y134 could be used
to elucidate the biological roles of PRMT5 and serve as a lead compound
for treatment of hematologic malignancies.
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hematological malignancy cell linesWestern blot assayscell cycle arrestDCBiological Assays Protein arginine methyltransferase 5hematologic malignanciesPRMT 5dimethylated levelstype II PRMT enzyme1.7 μ MStructure-Based Virtual ScreeningPRMT 5.IC 50 valueProtein Arginine Methyltransferase 5binding modebinding sitesmall-molecule inhibitorssubstrate arginine