Targeting the retinoid signaling pathway with YCT-529 for effective and reversible oral contraception in mice and primates

Nadja Mannowetz; Sanny S W Chung; Soma Maitra; Md Abdullah Al Noman; Henry L Wong; Narsihmulu Cheryala; Akash Bakshi; Debra J Wolgemuth; Gunda I Georg

doi:10.1038/s43856-025-00752-7

Targeting the retinoid signaling pathway with YCT-529 for effective and reversible oral contraception in mice and primates

Commun Med (Lond). 2025 Mar 13;5(1):68. doi: 10.1038/s43856-025-00752-7.

Authors

Affiliations

¹ YourChoice Therapeutics, 2261 Market Street, Unit 4762, San Francisco, CA, 94114, USA.
² Department of Genetics and Development, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
³ Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN, 55414, USA.
⁴ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
⁵ The Institute of Human Nutrition, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
⁶ The Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
⁷ Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN, 55414, USA. georg@umn.edu.

^# Contributed equally.

Abstract

Background: The retinoic acid receptor alpha (Rarα) has been validated as a male contraceptive target by genetic knockouts resulting in male sterility. The effects on spermatogenesis in the absence of RARα resemble the loss of RAR signaling in vitamin A deficiency, and the mice are otherwise normal. The effects on spermatogenesis in animals treated orally with the dual RARα/RARγ antagonist BMS-189453 closely phenocopies the absence of RARα function. Notably, the resulting male sterility is reversible. We, therefore, wished to identify RARα-selective inhibitors for potential male non-hormonal contraception.

Methods: YCT-529 was investigated for RARα selective inhibition, physicochemical characteristics, oral bioavailability, and pharmacokinetic properties in mice and non-human primates. It was assessed in mouse mating trials to determine the most effective dosing regimen to induce infertility in male mice and in male non-human primates to reduce sperm levels.

Results: Characterization of YCT-529 shows suitable biochemical, physicochemical, and pharmacokinetic properties for in vivo testing. YCT-529 inhibits mouse fertility of male mice within 4 weeks of oral administration, correlating with disrupted spermatogenesis demonstrating specific inhibition of the RARα pathway. Within 6 weeks after cessation of dosing, mouse fertility reverses. Furthermore, YCT-529 inhibits sperm production in a non-human primate model within 2 weeks of oral dosing without adverse side effects. Within 10-15 weeks after cessation of dosing, non-human primates' sperm counts fully reverses.

Conclusions: These results lay the groundwork for evaluating YCT-529 in human clinical trials.

Plain language summary

There is currently no oral birth control option available to men to prevent pregnancy in their sexual partners. YCT-529 is a non-hormonal male contraceptive that could be a potential drug for men to take to prevent pregnancy. YCT-529 works by interfering with vitamin A signaling necessary for sperm production and fertility. Our study examined its effectiveness and side effects in mice and non-human primates. We show that this oral drug causes infertility in mice, which can be reversed after stopping its consumption. In male non-human primates, sperm production is inhibited (this is how the drug prevents pregnancy) within 2 weeks of starting YCT-529 without adverse side effects and the animals regain fertility after stopping treatment.

Abstract

Plain language summary

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