Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

PRMT5 plays important roles in diverse
cellular processes and is
upregulated in several human 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 μM) 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 Kd of 0.987 μM. 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.