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To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic\n                    <jats:italic>STK33<\/jats:italic>\n                    perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound.\n                  <\/jats:p>","DOI":"10.1126\/science.adl2688","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T14:03:18Z","timestamp":1716472998000},"page":"885-890","update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":39,"title":["Reversible male contraception by targeted inhibition of serine\/threonine kinase 33"],"prefix":"10.1126","volume":"384","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-9345","authenticated-orcid":true,"given":"Angela F.","family":"Ku","sequence":"first","affiliation":[{"name":"Center for Drug Discovery, Department of Pathology &amp; Immunology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1988-389X","authenticated-orcid":true,"given":"Kiran L.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery, Department of Pathology &amp; 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