A groundbreaking study has identified that targeting the STK33 protein can induce safe and reversible infertility in male mice, offering a promising pathway for developing nonhormonal male contraceptives.
The research, which highlights STK33 as a critical protein for male fertility in both humans and mice, demonstrated that an inhibitor targeting this kinase can successfully cause reversible infertility in male mice without toxic side effects or harm to reproductive functions. This discovery positions STK33 as a viable target for new drug development, pointing to a revolutionary approach to male contraception.
Contraception plays a crucial role in family planning, enabling individuals to choose if and when to conceive and how many children to have. However, advancements in male contraception have been stagnant in recent decades. Currently, there are no effective oral contraceptives available for men. While hormonal approaches for male contraception are under investigation in clinical trials and show promising results, none have been approved for widespread use.
Exploring Nonhormonal Alternatives in Contraception
Nonhormonal contraceptive targets are promising due to their potential for fewer side effects. However, the development of small-molecule nonhormonal inhibitors has been limited, with even fewer demonstrating contraceptive efficacy in preclinical models. The homozygous serine/threonine kinase 33 (STK33) is essential for male fertility. Previous studies have shown that mutations in STK33 result in infertility in both mice and men due to defective sperm motility and morphology, without other significant health issues, making STK33 a viable target for male contraception.
To identify STK33-specific inhibitors, Angela Ku and her team conducted a large-scale drug screening using a multibillion-compound collection of DNA-encoded chemical libraries. This screening uncovered several potent STK33-specific inhibitors. Ku and her colleagues obtained crystal structures of STK33 with some identified compounds and used this information for structure-guided molecule design. One of the most promising compounds, CDD-2807, was shown to reduce fertility in vivo in male mice. The findings indicated that CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in the brain, and induced a contraceptive effect that mirrored genetic STK33 perturbations without altering testis size.
Crucially, the researchers found that the contraceptive effects of the inhibitor were reversible, and male mice recovered their fertility soon after the treatment was discontinued. “Any potential contraceptive drug must undergo extensive testing to demonstrate high efficacy and rule out adverse effects on hormone levels, overall reproductive function, and impact on offspring. Additionally, long-term studies are necessary to evaluate potential risks associated with prolonged use,” wrote Jerrett Holdaway and Gunda Georg in a related Perspective. Nevertheless, the findings substantiate the essential role of STK33 in male fertility and provide compelling evidence that this target is druggable and results in reversible male infertility.
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