Discovery of MOMA-341, a chemically distinct, potent and selective covalent inhibitor of Werner Syndrome Helicase (WRN) in clinical development

MOMA-341 is a chemically distinct, potent and selective clinical stage covalent inhibitor of WRN. Leveraging MOMA's KNOWMATIC platform and the presence of cysteine 727 in an allosteric binding pocket, covalent inhibitors were designed to achieve high potency. Optimization was based on precise refinement of covalent warhead trajectory, compound rigidity, and improvement of binding affinity to drive high kinact/KI. Optimization of potency and ADME properties, guided by in silico prediction of in vivo target occupancy, led to the discovery of MOMA-341, which demonstrates tumor regression at low doses in MSI-H mouse xenograft models. MOMA-341 is currently in clinical development.