Sepideh Salehipour-Bavarsad, Christian Iking, Jonas Kammertöns, Caroline Bouchard, Marion Meixner, Michael Daude, Wieland Steinchen, Felix Terwesten, Johanna Senst, David Vonhören, Sinja Rakow, Anne Kagerhuber, Sona Martirosian, Katrin Roth, Daniel Hilger, Stefanie Dörr, Gina Bach, Van Tuan Trinh, Anett Hauser, Frank Abendroth, Olalla Vázquez, Gert Bange, Jörg Walter Bartsch, Detlef Klaus Bartsch, Peter Kolb, Wibke E Diederich, Uta-Maria Bauer
A substantial body of research implicates PRMTs in the pathogenesis of human diseases, primarily as oncoproteins or tumor suppressors in cancer. 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. SAR analyses led to the design and synthesis of derivatives with increased potency in activating PRMT1 compared to TR-07 but at the cost of selectivity. 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 models. Our results establish TR-07 as the first selective, cell-active PRMT1 activator and underscore the therapeutic promise of this novel class of modulators.