Although birth control has been around for decades, almost none of the options specifically target sperm. Researchers are currently developing approaches that target testosterone or otherwise interrupt the sperm’s ability to fertilize an egg, but these may not work for everyone. But now researchers who publish in ACS’ Journal of Medicinal Chemistry have identified a new candidate molecule that might become an effective non-hormonal contraceptive for many people who produce sperm.
Previously, Gunda I. Georg and colleagues studied non-hormonal contraceptive options because testosterone-targeting approaches produced undesirable side effects. They developed a drug that targeted a specific vitamin A receptor and found that it worked as a very effective contraceptive with no side effects. But many proteins are involved in sperm formation, and exploring several options would help increase the likelihood that one would make it to human clinical trials and possibly the market.
Another set of proteins involved in the cell cycle are cyclin-dependent kinases, or CDKs, which play a role in sperm production and tumor development. Mice without the CDK2 receptor are sterile, so a drug that targets this protein might serve as an effective contraceptive. It also has potential as a cancer therapeutic because inhibiting the enzyme has slowed tumor growth in previous studies. However, CDK2 is very similar in shape to other enzymes in its family, and currently available inhibitors tend to produce unwanted off-target effects by accidentally binding others as well. So, Georg and his team wanted to develop a drug that might selectively inhibit CDK2 to serve as another contraceptive option.
The team previously discovered an unknown binding site in CDK2 and a commercially available dye molecule that successfully bound to it. Using the dye as a starting point, the researchers sifted through tens of thousands of different compounds in their current work to find those that bound the pocket equally well. They narrowed the list down to just three, choosing one to further optimize. The best version, named EF-4-177, demonstrated a long half-life and good diffusion in mouse testes. After 28 days of exposure, the animals’ sperm count decreased by approximately 45%. Additionally, EF-4-117 bound much more strongly to the CDK2 pocket than the dye, making it the highest affinity inhibitor for this site reported to date. The researchers say this work proves the potential of this inhibitor for future therapeutic applications.
Les auteurs reconnaissent le financement du Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), du National Institute of Health, du National Institute of General Medical Sciences et du National Cancer Institute.
