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
  • 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.
PMID: 38781365 DOI: 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.

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