Reversible male contraception by targeted inhibition of serine/threonine kinase 33

Science. 2024 May 24;384(6698):885-890. doi: 10.1126/science.adl2688. Epub 2024 May 23.

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.

MeSH terms

  • Animals
  • Blood-Testis Barrier / metabolism
  • Contraception* / methods
  • Contraceptive Agents, Male* / chemistry
  • Contraceptive Agents, Male* / pharmacology
  • Humans
  • Male
  • Mice
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases* / antagonists & inhibitors
  • Protein Serine-Threonine Kinases* / chemistry
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology
  • Structure-Activity Relationship
  • Testis / drug effects

Substances

  • Contraceptive Agents, Male
  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • Small Molecule Libraries
  • STK33 protein, human
  • Stk33 protein, mouse