STK33

Serine/threonine kinase 33 (STK33) inhibition produces a reversible contraceptive effect in mice Researchers used DNA-Encoded Libraries (DELs) to screen billions of potential small-molecule inhibitors Research indicates a need for kinase drug discovery research beyond oncology applications MADISON, Wis.--(BUSINESS WIRE)-- Research published in Science reveals a new target for non-hormonal male contraception. The protein, a kinase called STK33, has been linked to infertility in male mice and humans. Researchers from Baylor College of Medicine, in collaboration with scientists at Promega Corporation, used DNA-Encoded Libraries (DELs) to screen billions of compounds and identify potent inhibitors that bind STK33. Their results show that STK33 inhibition produces a reversible contraceptive effect in mice, making the protein a promising sperm-specific target for further male contraceptive development. In addition, the studies show that the novel contraceptive molecule (CDD-2807) is safe when delivered to the male mice and only affects the function and morphology of the sperm. “This research addresses our clear societal need for more safe, affordable and reversible options for contraception,” says Matt Robers, Senior Research Scientist at Promega. “Moreover, it demonstrates exciting methods for accelerating kinase drug discovery efforts in many areas.” Many kinase inhibitors have been developed to treat various forms of cancer. However, members of the protein kinase family play pivotal roles in many aspects of human biology. Of the 538 kinases in the human genome, 160, including STK33, are considered “dark kinases” due to a lack of existing research on their structure and function. This landmark Science paper demonstrates the importance of kinase research beyond oncology to uncover new therapeutic opportunities. The researchers used Promega NanoBRET Target Engagement Assays to characterize compound binding in live cells. In particular, the authors used the newly launched NanoBRET Target Engagement K192 Kinase Selectivity System to study the selectivity of the CDD-2807 inhibitor compound against a panel of 192 full-length kinases. Contributions from Promega researchers, including Robers and Jennifer Wilkinson, were integral to this publication by Martin M. Matzuk and his team at Baylor College of Medicine. Read the full article in Science here. Learn more about NanoBRET Target Engagement here. About Promega Corporation Promega Corporation is a leader in providing innovative solutions and technical support to the life sciences industry. The company’s portfolio of over 4,000 products supports a range of life science work across areas such as cell biology; DNA, RNA and protein analysis; drug development; human identification and molecular diagnostics. These tools and technologies have grown in their application over the last 45 years and are used today by scientists and technicians in labs for academic and government research, forensics, pharmaceuticals, clinical diagnostics and agricultural and environmental testing. Promega is headquartered in Madison, WI, USA with branches in 16 countries and over 50 global distributors. Learn more at . View source version on businesswire.com: Contacts Penny Patterson VP, Corporate Affairs Promega Corporation Phone: (608) 274-4330 E-mail: penny.patterson@promega.com Source: Promega Corporation View this news release online at:

None of the treated mice lost weight or died during the study, a sign that the treatment was safe. A novel, non-hormonal reversible contraceptive for men appears to be effective in mice, based on the results of a study sponsored by biological analysis company Promega.  Reporting May 23 in Science, researchers from Baylor College of Medicine and Lawrence Berkeley National Laboratory described how they developed a small molecule inhibitor called CDD-2807 that reduced fertility in male mice without any signs of toxicity. When the mice were taken off the drug, their fertility returned.  Synthetic derivatives of testosterone called dimethandrolone undecanoate (DMAU) and 11b-MNTDC are being tested as reversible male contraceptives in clinical trials but there are concerns about side effects, many of which overlap with those linked to birth control for women. On the preclinical side, researchers have looked at repurposing a cancer drug and targeting the retinoic acid receptor among other strategies, though none aside from the synthetic testosterone have made it to humans yet.  The Baylor team’s drug represents an entirely new strategy. The scientists pulled from nature’s playbook by hunting for compounds that inhibit serine/threonine kinase 33 (STK33), an enzyme that when mutated causes male sterility in both humans and mice. A screen of a multibillion-compound DNA-encoded drug library gave them a handful of potential contenders, which they used to design CDD-2807.  To see if the drug would work, the researchers tested it in male mice, following two different protocols to do so. In the first, they injected six mice intraperitoneally with a control solution and six with CDD-2807 twice daily at 15 mg/kg for 21 days, then placed them with fertile female mice. A month later, nearly all the mice in the control group sired at least seven offspring per female on average. While four of the six mice in the CDD-2807 group also had offspring, the litters were much smaller—less than one pup per female. By the second month, all the mice in the control group sired large litters but none of the treated mice did.  In the second protocol, the mice in the experimental group were given CDD-2807 once a day, but at 50 mg/kg. All the mice in the control group had pups—again, at least seven on average per female—while one mouse in the experimental group produced a single pup. No pups were born to any of the treated mice in the second month.  The researchers studied the drug’s reversibility by stopping it and then placing some of the mice in each group with new mates. For the mice in the first protocol, the one with the lower dose given twice daily, all of the mice in the experimental group had pups within the first month, with litter sizes on par with controls. Treated mice in the second protocol ultimately sired large litters too, but took about two months to do so.  None of the treated mice lost weight or died during the study, a sign that the treatment was safe. The size of their testis didn’t change either, a side effect that has been seen with other male contraceptive drugs that have been studied in mice. “These findings provide substantial support that targeted nonhormonal approaches can be effective in the development of a male contraceptive pill,” the researchers wrote in the abstract of their article. While the results point toward efficacy, only human studies will show whether it’s a viable candidate for male contraception, as graduate student Jarrett Holdaway and Gunda Georg, Ph.D., both of the University of Minneapolis College of Pharmacy and unaffiliated with the research, pointed out in a commentary that ran in Science along with the article. The drug will also need to be taken by mouth, not injected, to be commercially viable. “A successful male contraceptive pill needs to be orally bioavailable, which has been a challenge for several drug candidates,” Holdaway and Georg wrote. “Additionally, a male contraceptive pill … must navigate substantial safety hurdles before being considered for approval.” That includes long-term safety as well, they added.  The researchers plan to continue studying CDD-2807 as a therapeutic target and to come up with other versions of the drug that they’ll test in primates, the press release said.