Reversible male contraception by targeted inhibition of serine/threonine kinase 33

• 成果类型: Article
• 署名作者: Ku, Angela F.; Sharma, Kiran L.; Ta, Hai Minh; Sutton, Courtney M.; Bohren, Kurt M.; Wang, Yong; Chamakuri, Srinivas; Chen, Ruihong; Hakenjos, John M.; Jimmidi, Ravikumar; Kent, Katarzyna; Li, Feng; Li, Jian-Yuan; Ma, Lang; Madasu, Chandrashekhar; Palaniappan, Murugesan; Palmer, Stephen S.; Qin, Xuan; Robers, Matthew B.; Sankaran, Banumathi; Tan, Zhi; Vasquez, Yasmin M.; Wang, Jian; Wilkinson, Jennifer; Yu, Zhifeng; Ye, Qiuji; Young, Damian W.; Teng, Mingxing; Kim, Choel; Matzuk, Martin M.
• 署名单位: Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Promega Corporation; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10992
• DOI: 10.1126/science.adl2688
• 发表日期: 2024-05-24
• 页码: 885-890
• 关键词: sequence alignment; male-fertility; stk33; potent; DISCOVERY; carcinoma; MODEL

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.