Discovery of novel selective PRMT5-MTA inhibitors through structure-based virtual screening

The PRMT5-MTA complex, which is uniquely present in cancer cells with MTAP gene deletions, represents a compelling target for synthetic lethality strategies in cancer therapy. Despite the identification of PRMT5-MTA inhibitors to date, none have advanced to clinical use, and the chemical diversity among these inhibitors remains limited. Therefore, there is a pressing need for structurally novel inhibitors. Herein, we reported the discovery of new PRMT5-MTA inhibitors identified through structure-based virtual screening. Among these, Compound 14 demonstrated a binding affinity (K_D) of 236 nM for the PRMT5-MTA complex, exhibiting 12.0-fold selectivity over the PRMT5-SAM complex as determined by SPR (MTA+ K_D = 0.236 μM, SAM+ K_D = 2.84 μM, ratio = 12.0×) and a stronger inhibitory effect on PRMT5 enzyme activity in the presence of MTA. Molecular dynamics (MD) simulations provided insights into the binding mode of Compound 14 with the PRMT5 protein, facilitating the identification of derivatives 88 and 108, thereby expanding the chemical space of hit compounds. Our findings could not only enhance the chemical diversity of PRMT5-MTA selective inhibitors, but also deepen the understanding of the structure-activity relationship (SAR) governing PRMT5 selectivity. The discovered compounds represent promising starting points for the development and optimization of novel PRMT5-MTA inhibitors.