The world’s population has increased by more than 2.6-fold in the last 60 years, with projections indicating that it will grow to 9 billion by 2037 from 8 billion in 2022. These figures highlight the importance of family planning, yet there have been limited advances in contraception over recent decades. Specifically, there are no oral contraceptive pills available for men.
In a study published in the journal Science, researchers at Baylor College of Medicine and collaborating institutions demonstrated in animal models that a novel, non-hormonal sperm-specific approach could offer a promising option for reversible male contraception.
“Although researchers have been investigating several strategies to develop male contraceptives, we still do not have a birth control pill for men,” said corresponding author Dr. Martin Matzuk, director of the Center for Drug Discovery and chair of the Department of Pathology and Immunology at Baylor. “In this study we focused on a novel approach – identifying a small molecule that would inhibit serine/threonine kinase 33 (STK33), a protein that is specifically required for fertility in both men and mice.”
Previous research has shown that STK33 is enriched in the testis and is essential for forming functional sperm. In mice, knocking out the Stk33 gene results in sterility due to abnormal sperm and poor sperm motility. Similarly, men with mutations in the STK33 gene experience infertility caused by comparable sperm defects without other health issues or changes in testis size.
“STK33 is therefore considered a viable target with minimal safety concerns for contraception in men,” said Matzuk. “STK33 inhibitors have been described but none are STK33-specific or potent enough to disrupt STK33 function effectively.”
To find an effective STK33 inhibitor, researchers used DNA-Encoded Chemistry Technology (DEC-Tec) to screen their multi-billion compound collection. “Our group and others have used this approach before to uncover potent and selective kinase inhibitors,” said first author Dr. Angela Ku.
The team discovered potent STK33-specific inhibitors and generated modified versions to enhance stability, potency, and selectivity. Among these modifications, compound CDD-2807 proved most effective.
“Next, we tested the efficacy of CDD-2807 in our mouse model,” said co-author Dr. Courtney M. Sutton. The compound successfully crossed the blood-testis barrier and reduced sperm motility and numbers at low doses without signs of toxicity or accumulation in the brain.
Importantly, the contraceptive effect was reversible; after discontinuing CDD-2807 treatment, mice regained normal sperm motility and fertility.
“In our paper, we also present the first crystal structure for STK33,” said co-author Dr. Choel Kim. This structural insight enabled further refinement of CDD-2807’s drug-like properties.
“This study was a tour de force by our team at Baylor's Center for Drug Discovery," noted co-author Dr. Mingxing Teng.
Looking ahead, Matzuk stated: “In the next few years, our goal is to further evaluate this STK33 inhibitor and compounds similar to CDD-2807 in primates to determine their effectiveness as reversible male contraceptives.”
Additional co-authors affiliated with Baylor College of Medicine include Kiran L. Sharma et al., while Matthew B. Robers and Jennifer Wilkinson are affiliated with Promega Corp., and Banumathi Sankaran is affiliated with Lawrence Berkeley National Laboratory.
For financial support details regarding this work, refer to the publication.
___
