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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.
AuthorsKongkai Zhu, Hongrui Tao, Jia-Li Song, Lu Jin, Yuanyuan Zhang, Jingqiu Liu, Zhifeng Chen, Cheng-Shi Jiang, Cheng Luo, Hua Zhang
JournalBioorganic chemistry (Bioorg Chem) Vol. 81 Pg. 289-298 (12 2018) ISSN: 1090-2120 [Electronic] United States
PMID30172110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Benzylidene Compounds
  • Thiazoles
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
Topics
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Benzylidene Compounds (chemistry, pharmacology)
  • Binding Sites
  • Cell Line, Tumor
  • Databases, Chemical
  • G1 Phase Cell Cycle Checkpoints (drug effects)
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein-Arginine N-Methyltransferases (antagonists & inhibitors, chemistry)
  • Structure-Activity Relationship
  • Thiazoles (chemistry, pharmacology)

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