2. Academic Validation
  3. Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors

Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors

  • J Med Chem. 2022 Oct 27;65(20):13793-13812. doi: 10.1021/acs.jmedchem.2c01000.
Andrew M Asberry 1 2,  Xinpei Cai 3,  Xuehong Deng 1,  Ulises Santiago 4,  Sheng Liu 5 6,  Hunter S Sims 3,  Weida Liang 3,  Xueyong Xu 7,  Jun Wan 5 6 8,  Wen Jiang 7 9,  Carlos J Camacho 4,  Mingji Dai 3 9 10,  Chang-Deng Hu 1 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3 Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
  • 5 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
  • 6 The Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana 46202, United States.
  • 7 Department of Biological Sciences, Purdue University, 240 S Martin Jischke Drive, West Lafayette, Indiana 47907, United States.
  • 8 The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
  • 9 Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
  • 10 Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
PMID: 36206451 DOI: 10.1021/acs.jmedchem.2c01000
Abstract

Protein arginine methyltransferase 5 (PRMT5) is a master epigenetic regulator and an extensively validated therapeutic target in multiple cancers. Notably, PRMT5 is the only PRMT that requires an obligate cofactor, methylosome protein 50 (MEP50), to function. We developed compound 17, a novel small-molecule PRMT5:MEP50 protein-protein interaction (PPI) inhibitor, after initial virtual screen hit identification and analogue refinement. Molecular docking indicated that compound 17 targets PRMT5:MEP50 PPI by displacing the MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel. In vitro analysis indicates IC50 < 500 nM for prostate and lung Cancer cells with selective, specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression, and RNA-seq analysis suggests that compound 17 may dysregulate TGF-β signaling. Compound 17 provides a proof of concept in targeting PRMT5:MEP50 PPI, as opposed to catalytic targeting, as a novel mechanism of action and supports further preclinical development of inhibitors in this class.

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