An Internal Sulfur–Lone Pair Interaction Enabled the Discovery of Potent and Sub‐Family Selective PKMYT1 Inhibitors

Dysregulation of the serine/threonine kinase PKMYT1 contributes to the progression and therapy resistance of multiple aggressive cancers. However, developing selective inhibitors remains challenging due to the high conservation of kinase active sites. Herein, we report the rational design and characterization of a novel PKMYT1 inhibitor A4 that uniquely leverages an underutilized sulfur-lone pair interaction to achieve exceptional potency and favorable ADME properties. Our study not only expands the structural diversity of PKMYT1 inhibitors but also demonstrates the broader potential of nonbonding interaction engineering in small-molecule drug design.