Publication Date
5-24-2024
Journal
Science
DOI
10.1126/science.adl2688
PMID
38781365
PMCID
PMC11842024
PubMedCentral® Posted Date
2-20-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Humans, Male, Mice, Blood-Testis Barrier, Contraceptive Agents, Male, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Small Molecule Libraries, Testis, Contraception, Structure-Activity Relationship
Abstract
Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. 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 STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound.
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Immunology of Infectious Disease Commons, Immunopathology Commons, Medical Immunology Commons, Pathology Commons