作者
Angela F. Ku,Kiran 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 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
摘要
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.