A reversible male contraceptive method was developed by targeting the serine/threonine kinase 33 (STK33). Researchers identified potent STK33-specific inhibitors through DNA-encoded chemical library screening, leading to the development of CDD-2807, a compound with nanomolar potency and favorable metabolic stability. In mice, CDD-2807 showed no toxicity, efficiently crossed the blood-testis barrier, and induced a reversible contraceptive effect that mimicked genetic STK33 mutations without altering testis size. STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound. The study highlights the importance of contraception in family planning, especially for men, as current options are limited. Despite this, no effective oral contraceptive pills for men exist, and clinical trials for hormonal analogs are ongoing. STK33, a testis-enriched kinase, is essential for male germ cell function, and mutations in STK33 cause infertility. CDD-2807, a potent and selective STK33 inhibitor, was developed through medicinal chemistry efforts to improve its metabolic stability and selectivity. It demonstrated high affinity for STK33 and low activity against other kinases. The crystal structure of the STK33/CDD-2211 complex was determined, providing insights into the binding mechanism. CDD-2807 was tested in mice and showed a reversible contraceptive effect, with fertility restored after discontinuation. It did not cause significant testis size changes or liver enzyme elevation, indicating safety. CDD-2807 also reduced sperm motility and morphology, consistent with STK33 function. The compound's effects were reversible, with fertility resuming within days after treatment cessation. The study demonstrates that STK33 is a viable target for male contraception, and CDD-2807 is a promising candidate. The findings suggest that kinases can serve as beneficial targets for treating human conditions beyond oncology. The research underscores the potential of kinase inhibitors for developing safe and effective male contraceptives.A reversible male contraceptive method was developed by targeting the serine/threonine kinase 33 (STK33). Researchers identified potent STK33-specific inhibitors through DNA-encoded chemical library screening, leading to the development of CDD-2807, a compound with nanomolar potency and favorable metabolic stability. In mice, CDD-2807 showed no toxicity, efficiently crossed the blood-testis barrier, and induced a reversible contraceptive effect that mimicked genetic STK33 mutations without altering testis size. STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound. The study highlights the importance of contraception in family planning, especially for men, as current options are limited. Despite this, no effective oral contraceptive pills for men exist, and clinical trials for hormonal analogs are ongoing. STK33, a testis-enriched kinase, is essential for male germ cell function, and mutations in STK33 cause infertility. CDD-2807, a potent and selective STK33 inhibitor, was developed through medicinal chemistry efforts to improve its metabolic stability and selectivity. It demonstrated high affinity for STK33 and low activity against other kinases. The crystal structure of the STK33/CDD-2211 complex was determined, providing insights into the binding mechanism. CDD-2807 was tested in mice and showed a reversible contraceptive effect, with fertility restored after discontinuation. It did not cause significant testis size changes or liver enzyme elevation, indicating safety. CDD-2807 also reduced sperm motility and morphology, consistent with STK33 function. The compound's effects were reversible, with fertility resuming within days after treatment cessation. The study demonstrates that STK33 is a viable target for male contraception, and CDD-2807 is a promising candidate. The findings suggest that kinases can serve as beneficial targets for treating human conditions beyond oncology. The research underscores the potential of kinase inhibitors for developing safe and effective male contraceptives.