1. Academic Validation
  2. Reversible male contraception by targeted inhibition of serine/threonine kinase 33

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

  • Science. 2024 May 24;384(6698):885-890. doi: 10.1126/science.adl2688.
Angela F Ku 1 Kiran L Sharma # 1 Hai Minh Ta # 1 2 Courtney M Sutton # 1 Kurt M Bohren 1 Yong Wang 1 Srinivas Chamakuri 1 Ruihong Chen 1 John M Hakenjos 1 Ravikumar Jimmidi 1 Katarzyna Kent 1 3 Feng Li 1 2 Jian-Yuan Li 1 Lang Ma 1 Chandrashekhar Madasu 1 Murugesan Palaniappan 1 Stephen S Palmer 1 Xuan Qin 1 Matthew B Robers 4 Banumathi Sankaran 5 Zhi Tan 1 2 Yasmin M Vasquez 1 Jian Wang 1 Jennifer Wilkinson 4 Zhifeng Yu 1 Qiuji Ye 1 Damian W Young 1 2 Mingxing Teng 1 2 Choel Kim 1 2 Martin M Matzuk 1 2 3
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Promega Corporation, Madison, WI 53711, USA.
  • 5 Molecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • # Contributed equally.
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.

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