The world population has increased more than 2.6 times in the last 60 years and this growing trend continues, so it is estimated that the number of people on our planet will reach 9 billion by 2037, from 8 billion in 2022. These figures highlight the need to consider family planning; However, in recent decades there have been few advances in contraception and, specifically, there are no oral contraceptive pills for men.
This could change thanks to the results obtained in a new study that has been published in the journal Science and in which researchers from Baylor College of Medicine and other collaborating institutions have demonstrated in animal models that a novel, non-hormonal and specific approach for sperm, offers a promising option for reversible male contraception.
“Although several strategies have been investigated to develop male contraceptives, we still do not have a birth control pill for men,” said Dr. Martin Matzuk, director of the Center for Drug Discovery and chair of the Department of Pathology and Immunology at Baylor and senior author. . “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 testes and is essential for the formation of functional sperm. In mice, deletion of the Stk33 gene causes sterility due to abnormal sperm and low sperm motility. In men, a mutation in the STK33 gene leads to infertility caused by the same sperm defects found in mice without the Stk33 gene. The most important thing is that both mice and men with these mutations do not have other defects and have normal testicular size.
“Therefore, STK33 is considered a viable target with minimal safety concerns for contraception in men,” said Matzuk, who has been on the Baylor faculty for 30 years and holds the Stuart A. Wallace and Robert L. Moody Professorships. , Sr. in Pathology and Immunology. “STK33 inhibitors have been described, but none are specific for STK33, nor potent enough to chemically disrupt STK33 function in living organisms.”
An effective, safe and reversible male contraceptive
“We used DNA-Encoded Chemistry Technology (DEC-Tec) to screen our collection of billions of compounds and discover potent inhibitors of STK33,” said first author Dr. Angela Ku, a scientist in Matzuk’s lab. “Our group and others have used this approach previously to discover potent and selective kinase inhibitors.”
The researchers discovered specific inhibitors of STK33, of which they generated modified versions to make them more stable, potent and selective. “Among these modified versions, the CDD-2807 compound turned out to be the most effective,” Ku said. “Next, we tested the efficacy of CDD-2807 in our mouse model,” said co-author Dr. Courtney M. Sutton, a postdoctoral researcher in Matzuk’s lab. “We evaluated various doses and treatment schedules and then determined sperm motility and number in the mice, as well as their ability to fertilize females.”
“The mice showed no signs of toxicity from treatment with CDD-2807, the compound did not accumulate in the brain and the treatment did not alter the size of the testes”
The compound CDD-2807 effectively crossed the blood-testis barrier and reduced sperm motility and number, as well as fertility in mice at low doses. “We were pleased to see that the mice showed no signs of toxicity from CDD-2807 treatment, that the compound did not accumulate in the brain, and that the treatment did not alter the size of the testes, similar to mice without the Stk33 gene and men with the STK33 mutation,” Sutton said. “Most importantly, the contraceptive effect was reversible. After a period without the CDD-2807 compound, the mice regained motility and sperm number and became fertile again.”
“In our paper, we also present the first crystal structure of 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 showed how one of our potent inhibitors interacts with the STK33 kinase in three dimensions. “This allowed us to model and design our final compound, CDD-2807, to improve its properties as a drug.” “In the coming years, we aim to further evaluate this STK33 inhibitor and CDD-2807-like compounds in primates to determine their efficacy as reversible male contraceptives,” concludes Matzuk.
