A promising approach to developing birth control pills for men

Over the past 60 years, the world's population has increased by more than 2.6 times. This growth continues, with projections showing the population will reach 9 billion by 2037, up from 8 billion in 2022. These figures highlight the need for family planning; however, there have been few contraceptive breakthroughs in recent decades. This is especially true for men, for whom oral contraceptive pills have not yet been developed.

In a study published in Science, scientists from Baylor College of Medicine and their colleagues demonstrated in animal models that a new, non-hormonal, sperm-specific method offers promise option of reversible male contraception.

"Despite the fact that researchers have long been working on developing male contraceptives, we still do not have a birth control pill for men," said lead study author Dr. Martin Matsuk, director of the Center for Drug Research and chair of the Department of Pathology and Immunology at the Medical School. Baylor College.

"In this study, we focused on a new approach - searching for a small molecule that would inhibit serine/threonine kinase 33 (STK33), a protein essential for fertility in both men and mice."

Previous studies have shown that STK33 plays a key role in the formation of functional sperm. Mice in which the Stk33 gene was knocked out experienced infertility due to abnormal sperm and poor sperm motility. In men, the STK33 gene mutation also leads to infertility for the same reasons. It is important to note that these mice and men have no other defects, and the size of the testes remains normal.

"STK33 is considered a promising target for contraception in men with minimal safety concerns," said Matsuk, who has been at Baylor College of Medicine for 30 years and holds several prestigious positions.

Searching for a Potent STK33 Inhibitor "We used DNA-encoded chemistry (DEC-Tec) technology to screen our collection of several billion compounds and discover potent STK33 inhibitors," said the study's first author, Dr. Angela Koo, a postdoctoral fellow in the Matsuka lab. "We and other groups have already used this approach to discover potent and selective kinase inhibitors."

Researchers have discovered potent STK33 inhibitors and created modified versions of them to make them more stable, potent and selective. "Among these modified versions, CDD-2807 was the most effective," Ku added.

“We then tested the effectiveness of CDD-2807 in our mouse model,” said study co-author Dr. Courtney M. Sutton, a postdoctoral fellow in the Matsuka lab. "We evaluated several doses and treatment schedules and then determined sperm motility and sperm count in mice, as well as their ability to fertilize females."

CDD-2807 effectively crossed the blood-testis barrier and reduced sperm motility, sperm count, and fertility in mice at low doses. “We were pleased to see that the mice showed no signs of toxicity from CDD-2807 treatment, the drug did not accumulate in the brain, and treatment did not alter testicular size as in Stk33 knockout mice and men with the STK33 mutation,” Sutton noted.

"The important point was that the contraceptive effect was reversible. After discontinuation of CDD-2807, the motility and sperm count in the mice were restored, and they became fertile again."

“In our paper, we also present the first crystal structure of STK33,” said study co-author Dr. Choel Kim, assistant professor of biochemistry and molecular pharmacology and member of the Dan L. Duncan Comprehensive Cancer Research Center at Baylor College of Medicine.

"Our crystal structure showed how one of our potent inhibitors interacts with STK33 kinase in three dimensions. This allowed us to model and develop our final drug CDD-2807 with better drug properties."

“This study was a breakthrough for our team at the Baylor Drug Discovery Center and our collaborators,” said study co-author Dr. Mingxing Teng, assistant professor of pathology and immunology and biochemistry and molecular pharmacology at Baylor College of Medicine. Teng is also a scientist at the Texas Cancer Research Institute and a member of the Dan L. Duncan Comprehensive Cancer Center at Baylor.

"By starting with a genetically validated contraceptive target, we were able to show that STK33 is also a chemically validated contraceptive target."

“In the coming years, our goal is to further evaluate this STK33 inhibitor and compounds like CDD-2807 in primates to determine their effectiveness as reversible male contraceptives,” Matsuk concluded.