New Male Contraceptive Reduces Sperm Count by 45% in Mice

A new molecule could offer non-hormonal contraceptive options for people who produce sperm, according to new research published in The American Chemical Society (ACS)’s Journal of Medicinal Chemistry.

Limited contraceptive options

People who produce sperm are currently limited to two forms of contraception – condoms, which can fail, and a vasectomy, a surgical procedure that is regarded as a permanent form of sterilization. A 2019 survey by the Male Contraceptive Initiative found that 70% of men in the United States aged 18–44 are “somewhat or very interested in new male contraception.”

“Scientists have been trying for decades to develop an effective male oral contraceptive, but there are still no approved pills on the market,” Dr. Abdullah Al Noman, a graduate student in the Georg lab, said. Most contraceptive drugs in preclinical development target the sex hormone testosterone, which can lead to adverse side effects including depression, weight gain and increased cholesterol levels. “We wanted to develop a non-hormonal male contraceptive to avoid these side effects,” Noman added.

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In 2022, the laboratory of Professor Gunda Georg at the University of Minnesota developed a drug –   YCT529 – that prevents pregnancy in mice by blocking a vitamin A receptor.

YCT529 is now in early-stage human clinical trials. However, the team at the Georg lab emphasize that, as there are a variety of proteins involved in the formation of sperm, exploring other drug options would increase the likelihood of at least one contraceptive for people who produce sperm making it to the market.

EF-4-177 reduces sperm count by 45% in mice

The researchers sought to develop a drug that inhibits a protein called cyclin-dependent kinase 2 (CDK2), which belongs to the cyclin-dependent kinase protein family. This family of proteins is involved in sperm cell production and tumor development. Mice lacking the CDK2 receptor are sterile, suggesting it could be an effective target for inhibition as a contraceptive. However, the receptor is structurally similar to other enzymes within the CDK family, therefore increasing the likelihood of off-target effects.

Georg and colleagues identified a previously unknown site in CDK2 and a dye molecule that binds to it. Using the dye, they screened several thousand compounds to identify any that selectively target the binding site.

They selected one molecule for further optimization: EF-4-177, which bound to CDK2 more strongly than the dye. Georg and team found that this compound demonstrated a long half-life in mice, and after 28 days’ exposure, the animals’ sperm count reduced by 45%. “This work details the discovery of the highest affinity allosteric CDK inhibitors reported and shows promise for this series to yield an efficacious and selective allosteric CDK2 inhibitor,” the researchers write.

In December, the University of Minnesota was awarded a $6.5 million contract by the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s (NICHD) Contraceptive Development Program (CDP) to develop reliable, reversible, affordable and safe contraceptive drugs.

“The world is ready for a male contraceptive agent, and we are happy to help make this a reality by working with NICHD,” said Georg.

This article is a rework of a press release issued by the American Chemical Society. Material has been edited for length and content.

Reference: Faber EB, Wang N, John K, et al. Screening through lead optimization of high affinity, allosteric cyclin-dependent kinase 2 (CDK2) inhibitors as male contraceptives that reduce sperm counts in mice. J Med Chem. 2023. doi: 10.1021/acs.jmedchem.2c0173.