Compound CDD-2807 effectively crossed the blood-testis barrier and reduced sperm motility and numbers and mice fertility at low doses. “We were pleased to see that the mice did not show signs of toxicity from CDD-2807 treatment, that the compound did not accumulate in the brain, and that the treatment did not alter testis size, similar to the Stk33 knockout mice and the men with the STK33 mutation,” Sutton said. “Importantly, the contraceptive effect was reversible. After a period without compound CDD-2807, the mice recovered sperm motility and numbers and were fertile again.”

“In our paper, we also present the first 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 showed how one of our potent inhibitors interacts with STK33 kinase in three dimensions. This enabled us to model and design our final compound, CDD-2807, for better drug-like properties.”

“This study was a tour de force by our team in the Center for Drug Discovery at Baylor and our collaborators,” said co-author Dr. Mingxing Teng, assistant professor of pathology and immunology and of biochemistry and molecular pharmacology at Baylor. Teng also is a Cancer Prevention Research Institute of Texas Scholar and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Starting with a genetically validated contraceptive target, we were able to show that STK33 is also a chemically validated contraceptive target.”

“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,” Matzuk said. 

Additional co-authors of the paper affiliated with Baylor College of Medicine are Kiran L. Sharma, Hai Minh Ta, Kurt M. Bohren, Yong Wang, Srinivas Chamakuri, Ruihong Chen, John M. Hakenjos, Ravikumar Jimmidi, Katarzyna Kent, Feng Li, Jian-Yuan Li, Lang Ma, Chandrashekhar Madasu, Murugesan Palaniappan, Stephen S. Palmer, Xuan Qin, Zhi Tan, Yasmin M. Vasquez, Jian Wang, Zhifeng Yu, Qiuji Ye and Damian W. Young. Co-authors Matthew B. Robers and Jennifer Wilkinson are affiliated with Promega Corp., and Banumathi Sankaran is affiliated with Lawrence Berkeley National Laboratory.

For financial support for this work, see the publication.