为了用STK33特异性抑制剂对丝氨酸/苏氨酸激酶33（STK33）进行化学评估，以达到男性避孕的目的，研究人员筛选了数十亿化合物的DNA编码化学文库，发现了强效的STK33特异性抑制剂，确定了与截短的命中CDD-2211结合的STK33激酶结构域，并生成了优化的命中CDD-2807，它具有纳摩尔细胞效力（半最大抑制浓度=9.2纳摩尔）和良好的代谢稳定性。
在小鼠体内，CDD-2807无毒性，能有效穿过血睾屏障，不在大脑中蓄积，并能诱导可逆的避孕效果，这种效果表征了STK33的遗传扰乱，而不会改变睾丸的大小。因此，STK33是一种经过化学验证的非激素避孕靶点，CDD-2807是一种有效的工具化合物。
据悉，纯合STK33突变的男性或小鼠会因精子形态和活力缺陷而不育。
附：英文原文
Title: Reversible male contraception by targeted inhibition of serine/threonine kinase 33
Author: 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
Issue&Volume: 2024-05-24
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.
DOI: adl2688
Source: https://www.science.org/doi/10.1126/science.adl2688