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Identification of 5-benzylidene-2-phenylthiazolones as potent PRMT5 inhibitors by virtual screening, structural optimization and biological evaluations.

Abstract：

:Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for glioblastoma and mantel cell lymphoma. In the present study, 11 novel PRMT5 inhibitors with 5-benzylidene-2-phenylthiazolone scaffold were identified by molecular docking-based virtual screening and structural optimization. Their IC50 values against PRMT5 at enzymatic level were ranging from 0.77 to 23 μM. As expected, the top two active hits (5 and 19) showed potent anti-proliferative activity against MV4-11 cells with EC50 values lower than 10 μM and reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. Besides, 5 and 19 demonstrated the mechanism of cell killing in cell cycle arrest and apoptotic effect. The probable binding modes of the two compounds were explored and further verified by molecular dynamics simulation. The structure-activity relationship (SAR) of this class of structures was also discussed and further demonstrated by molecular docking simulation.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Zhu K,Tao H,Song JL,Jin L,Zhang Y,Liu J,Chen Z,Jiang CS,Luo C,Zhang H

doi

10.1016/j.bioorg.2018.08.021

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

289-298

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(18)30654-0

journal_volume

81

pub_type

杂志文章

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