1. Reversible male contraception by targeted inhibition of serine/threonine kinase 33.
- Author
-
Ku AF, Sharma KL, Ta HM, Sutton CM, Bohren KM, Wang Y, Chamakuri S, Chen R, Hakenjos JM, Jimmidi R, Kent K, Li F, Li JY, Ma L, Madasu C, Palaniappan M, Palmer SS, Qin X, Robers MB, Sankaran B, Tan Z, Vasquez YM, Wang J, Wilkinson J, Yu Z, Ye Q, Young DW, Teng M, Kim C, and Matzuk MM
- Subjects
- Animals, Humans, Male, Mice, Blood-Testis Barrier metabolism, Testis drug effects, Structure-Activity Relationship, Contraceptive Agents, Male chemistry, Contraceptive Agents, Male pharmacology, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases chemistry, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Contraception methods
- 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.
- Published
- 2024
- Full Text
- View/download PDF