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

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.