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Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors
Andrew M Asberry1,2, Xinpei Cai3, Xuehong Deng1
1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
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.
Insights
Researchers developed compound 17, a novel inhibitor targeting the Protein Arginine Methyltransferase 5:Methylosome Protein 50 (PRMT5:MEP50) protein-protein interaction. This approach offers a new strategy for cancer therapy by disrupting essential epigenetic regulation.
Area of Science:
- Epigenetics
- Chemical Biology
- Cancer Therapeutics
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a key epigenetic regulator and a validated cancer target.
- PRMT5 function relies on its obligate cofactor, methylosome protein 50 (MEP50).
- Targeting the PRMT5:MEP50 interaction presents a novel therapeutic strategy.
Purpose of the Study:
- To develop and characterize a small-molecule inhibitor targeting the PRMT5:MEP50 protein-protein interaction (PPI).
- To evaluate the compound's efficacy and mechanism of action in cancer cells.
Main Methods:
- Virtual screening and analogue refinement to identify compound 17.
- Molecular docking to predict the binding mode.
- In vitro assays to assess inhibition of PRMT5:MEP50 activity and gene expression.
- RNA-sequencing (RNA-seq) to analyze downstream signaling pathways.
Main Results:
- Compound 17 selectively inhibits the PRMT5:MEP50 PPI with IC50 < 500 nM in prostate and lung cancer cells.
- Specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression was observed.
- RNA-seq data suggest compound 17 may dysregulate TGF-β signaling.
Conclusions:
- Compound 17 serves as a proof-of-concept for targeting the PRMT5:MEP50 PPI.
- This PPI inhibition represents a novel mechanism of action distinct from catalytic inhibition.
- Further preclinical development of PRMT5:MEP50 PPI inhibitors is warranted.
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