利用 YCT-529 靶向视黄醇信号通路,在小鼠和灵长类动物中实现有效、可逆的口服避孕。

IF 5.4 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Communications medicine Pub Date : 2025-03-13 DOI:10.1038/s43856-025-00752-7
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
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Targeting the retinoid signaling pathway with YCT-529 for effective and reversible oral contraception in mice and primates.

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.

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