Development of TSSK1 and TSSK2 Targeted Degraders Reveals Sperm Machinery for Protein Degradation and Potential for Nonhormonal Male Contraception

  • J Med Chem. 2026 Jun 25;69(12):14236-14254. doi: 10.1021/acs.jmedchem.5c03689.
Jerrett A Holdaway  1 ,  Lokesh Saini  2 ,  Raven Coil-Otto  1 ,  Saman Nayyab  2  3 ,  Mahboubeh Taghavi  2 ,  Pablo Visconti  2 ,  Gunda I Georg  1
Affiliations
  • 1. Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States.
  • 2. Department of Veterinary and Animal Sciences, University of Massachusetts-Amherst, Amherst, Massachusetts 01003, United States.
  • 3. Molecular and Cellular Biology Program, University of Massachusetts-Amherst, Amherst, Massachusetts 01003, United States.
PMID: 42228803 DOI: 10.1021/acs.jmedchem.5c03689
Abstract

We report the design, synthesis, and characterization of a series of targeted degraders directed against testis-specific serine/threonine kinases TSSK1 and TSSK2. A stable CHO-K1 cell line expressing HiBiT-tagged TSSK1 enabled quantitative cellular profiling and identified compound 5.1 as a potent TSSK1 degrader with a DC50 of 10 nM and a Dmax of 68% after 48 h. In contrast, ex vivo incubation of CD1 mouse sperm with degrader 5.4 induced up to an 80% reduction of the TSSK2 isoform within 4 h and translated into profound functional loss, resulting in a 97% reduction in sperm motility and near-complete loss of in vitro fertilization. Both alkyl- and PEG-linked degraders displayed metabolic N-dealkylation and high efflux, and therefore will require optimization. These data provide proof of concept that targeted degradation can occur within sperm cells, leading to a disruption of sperm function and encouraging further optimization toward in vivo evaluation for male contraception.

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