This study explores the potential of serine/threonine kinase 33 (STK33) as a target for male contraception. The authors screened a large compound library using DNA-encoded chemistry technology (DEC-Tec) and identified potent STK33-specific inhibitors. They optimized one of these inhibitors, CDD-2807, which demonstrated nanomolar cellular potency and favorable metabolic stability. In mice, CDD-2807 efficiently crossed the blood-testis barrier, induced a reversible contraceptive effect without altering testis size, and did not cause toxicity. The study also determined the crystal structure of the STK33 kinase domain bound with CDD-2211, providing insights into the molecular basis of the drug's action. The findings suggest that STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound for further research and development.This study explores the potential of serine/threonine kinase 33 (STK33) as a target for male contraception. The authors screened a large compound library using DNA-encoded chemistry technology (DEC-Tec) and identified potent STK33-specific inhibitors. They optimized one of these inhibitors, CDD-2807, which demonstrated nanomolar cellular potency and favorable metabolic stability. In mice, CDD-2807 efficiently crossed the blood-testis barrier, induced a reversible contraceptive effect without altering testis size, and did not cause toxicity. The study also determined the crystal structure of the STK33 kinase domain bound with CDD-2211, providing insights into the molecular basis of the drug's action. The findings suggest that STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound for further research and development.