Language

English

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

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.

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

Published Open-Access

yes

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