Small-Molecule Activators of PRMT1: Discovery, Optimization, and Proapoptotic Effects in Pancreatic Cancer Cells

Le résumé fourni par la source

A substantial and growing body of research implicates protein‑arginine methyltransferases (PRMTs) in the pathogenesis of a range of human diseases, most prominently cancer. Their role – as oncoproteins or tumor suppressors – depends on both the cellular context and the specific type of malignancy. Starting from structure-based in silico screening of small-molecule databases, we predicted, synthesized, and assayed compounds aimed at specifically inhibiting selected PRMT family members. Unexpectedly, among several PRMT-inhibitory molecules we identified TR-07, a compound that selectively enhances the catalytic activity of PRMT1 in vitro. The following structure-activity-relationship analyses led to the design and synthesis of derivatives that were more potent in activating PRMT1 than TR-07, but at the cost of selectivity relative to other PRMTs. Hydrogen/Deuterium Exchange mass spectrometry and protein-protein interaction assays revealed that TR-07 and its derivatives bind to the αY helix near the catalytic core of PRMT1. Treatment of pancreatic tumor cells with these PRMT1 activators enhanced global ADMA levels and augmented PRMT1’s apoptotic function in cell culture and mouse experiments. Our results establish TR-07 as the first selective, cell-active PRMT1 activator and underscore the therapeutic promise of this novel class of modulators, particularly in disease conditions where PRMT1 is linked to a more favorable outcome.

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