| First Author | Ku AF | Year | 2024 |
| Journal | Science | Volume | 384 |
| Issue | 6698 | Pages | 885-890 |
| PubMed ID | 38781365 | Mgi Jnum | J:352589 |
| Mgi Id | MGI:7707644 | Doi | 10.1126/science.adl2688 |
| Citation | Ku AF, et al. (2024) Reversible male contraception by targeted inhibition of serine/threonine kinase 33. Science 384(6698):885-890 |
| abstractText | 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. |
