Researchers have demonstrated in animal models that a new, non-hormonal method targeting sperm shows promise as a reversible form of male contraception. The world’s population has more than doubled in the past 60 years and is expected to reach 9 billion by 2037. This growth highlights the importance of family planning, but there have been few advances in contraception, especially for men. Currently, there are no oral contraceptive pills available for men.The journal Science published a study conducted by researchers at Baylor College of Medicine and collaborating institutions, which showed in animal models that a new, non-hormonal sperm-specific method could potentially provide a reversible option for male contraception. Dr. Martin Matzuk, the corresponding author and director of the Center for Drug Discovery and chair of the Department of Pathology and Immunology at Baylor, highlighted the lack of a male birth control pill and the need for new approaches. The study focused on a different method for male contraceptives.
Scientists have discovered a small molecule that can stop the activity of serine/threonine kinase 33 (STK33), a protein that plays a crucial role in fertility for both men and mice.”
Previous studies have revealed that STK33 is highly concentrated in the testis and is essential for the production of healthy sperm. In mice, deleting the Stk33 gene causes infertility due to abnormal sperm and low sperm motility. In humans, having a mutation in the STK33 gene results in infertility due to the same sperm problems observed in the Stk33 knockout mice. Importantly, mice and humans with these mutations do not have any other defects and even Men with mutations in the STK33 gene may have normal testis size.
Matzuk, a faculty member at Baylor for 30 years and Baylor’s Stuart A. Wallace Chair and Robert L. Moody, Sr. Chair of Pathology and Immunology, stated that STK33 is a promising target for male contraception with minimal safety concerns. He also mentioned that while STK33 inhibitors have been described, none are specific or potent enough to chemically disrupt STK33 function in living organisms.
Finding a potent STK33 inhibitor
The researchers used DNA-Encoded Chemistry Technology (DEC-Tec) to screen a multi-billion compound collection in order to discover powerful STK33 inhibitors.
Dr. Angela Ku, a staff scientist in the Matzuk lab, stated that their group and others have previously used this method to discover powerful and selective kinase inhibitors. The researchers found potent STK33-specific inhibitors, and then successfully created modified versions to improve their stability, potency, and selectivity. Among these modified versions, compound CDD-2807 was found to be the most effective, according to Ku.
Dr. Courtney M. Sutton, a postdoctoral fellow in the Matzuk lab, mentioned that they then tested the effectiveness of CDD-2807 in their mouse model. They evaluated multiple doses and determined that the compound was effective.The researchers established treatment schedules and then assessed the sperm motility and number in the mice, along with their ability to fertilize females. The compound CDD-2807 was successful in crossing the blood-testis barrier and lowering sperm motility and numbers, as well as reducing mice fertility at low doses. It was noted that the mice did not exhibit any signs of toxicity from the CDD-2807 treatment, and the compound did not accumulate in the brain. Furthermore, the treatment did not lead to any changes in testis size, similar to the Stk33 knockout mice and men with the STK33 mutation. The researchers also found that the contraceptive effect of CDD-2807 was reversible after a period without the compound.nd CDD-2807, the mice recovered sperm motility and numbers and became fertile again.”
“Our paper also presents the initial crystal structure for STK33,” said co-author Dr. Choel Kim, associate professor of biochemistry and molecular pharmacology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Our crystal structure revealed how one of our potent inhibitors interacts with STK33 kinase in three dimensions. This allowed us to model and design our final compound, CDD-2807, for improved drug-like properties.”
“This research was an impressive achievement by our team in the Center for Drug Discovery at Baylor and our collaborators.Co-author Dr. Mingxing Teng, who is an assistant professor of pathology and immunology and of biochemistry and molecular pharmacology at Baylor, as well as a Cancer Prevention Research Institute of Texas Scholar and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor, stated, “Starting with a genetically validated contraceptive target, we were able to show that STK33 is also a chemically validated contraceptive target.” The goal in the coming years is to further assess the STK33 inhibitor and compounds similar to CDD-2807 in primates to determine their effectiveness as reversible male contraceptives,” Matzuk said.
Â
