Angela F. Ku; Kiran L. Sharma; Hai Minh Ta; Courtney M. Sutton; Kurt M. Bohren; Yong Wang; Srinivas Chamakuri; Ruihong Chen; John M. Hakenjos; Ravikumar Jimmidi; Katarzyna Kent; Feng Li; Jian-Yuan Li; Lang Ma; Chandrashekhar Madasu; Murugesan Palaniappan; Stephen S. Palmer; Xuan Qin; Matthew B. Robers; Banumathi Sankaran; Zhi Tan; Yasmin M. Vasquez; Jian Wang; Jennifer Wilkinson; Zhifeng Yu; Qiuji Ye; Damian W. Young; Mingxing Teng; Choel Kim; Martin M. Matzuk
Science, 2024, 384(6698), 885-890
https://doi.org/10.1126/science.adl2688

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.