1. Reversible male contraception by targeted inhibition of serine/threonine kinase 3.
- Author
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Ku, Angela F., Sharma, Kiran L., Hai Minh Ta, Sutton, Courtney M., Bohren, Kurt M., Yong Wang, Chamakuri, Srinivas, Ruihong Chen, Hakenjos, John M., Jimmidi, Ravikumar, Kent, Katarzyna, Feng Li, Jian-Yuan Li, Lang Ma, Madasu, Chandrashekhar, Palaniappan, Murugesan, Palmer, Stephen S., Xuan Qin, Robers, Matthew B., and Sankaran, Banumathi
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CONTRACEPTION , *SERINE , *CHEMICAL libraries , *SPERM motility , *SPERMATOGENESIS , *CONTRACEPTIVES , *THREONINE - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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