MD_DATA_PRMT_5

The PRMT5-MTA complex, which is uniquely present in cancer cells with <i>MTAP </i>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 report the discovery of new PRMT5-MTA inhibitors identified through structure-based virtual screening. Among these, compound <b>14</b> demonstrated subnanomolar binding affinity for the PRMT5-MTA complex with 11.7-fold selectivity over the PRMT5-SAM complex (MTA+ <i>K</i>_D = 0.236 μM, SAM+ <i>K</i>_D = 2.77 μM, ratio = 11.7×). Molecular dynamics (MD) simulations provided insights into the binding mode of compound <b>14</b> with the PRMT5 protein, facilitating the identification of derivatives <b>88 </b>and <b>108</b>, thereby expanding the chemical space of hit compounds. Our findings 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.