Abstract 2611 Unveiling Potent Inhibitors for Protein N-terminal Methyltransferase

This study aimed to develop cell-active and selective inhibitors to investigate the biological role of NTMT1 catalytic activity. Through high-throughput screening, venglustat, a known allosteric inhibitor of ceramide glycosyltransferase, was identified as a potent inhibitor (IC50 = 0.42 μM) of NTMT1, with significant selectivity over 36 other methyltransferases. The crystal structure of NTMT1-venglustat revealed that venglustat competitively binds at the peptide substrate site, effectively reducing protein N-terminal methylation in cells (IC50 = 0.5 μM).