Development of the retinoic acid receptor alpha-specific antagonist YCT-529 for male contraception: A brief review

Rui Shi; Debra J Wolgemuth; Gunda I Georg

doi:10.1016/j.contraception.2024.110809

Development of the retinoic acid receptor alpha-specific antagonist YCT-529 for male contraception: A brief review

Contraception. 2025 Jan 3:110809. doi: 10.1016/j.contraception.2024.110809. Online ahead of print.

Authors

Rui Shi¹, Debra J Wolgemuth², Gunda I Georg³

Affiliations

¹ Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, 55414, United States.
² Department of Genetics and Development, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, United States; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, United States; The Institute of Human Nutrition, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, United States; The Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, United States. Electronic address: [email protected].
³ Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, 55414, United States. Electronic address: [email protected].

PMID: 39756562
DOI: 10.1016/j.contraception.2024.110809

Abstract

Genetic studies in mice have demonstrated that retinoic acid receptor alpha (RARα) deficiency leads to male infertility without affecting overall viability, suggesting that pharmacological inhibition of this receptor could be a viable contraceptive strategy. This review describes the use of experimental approaches to develop RARα-selective antagonists for male contraception. Initial studies with BMS-189453, a pan-RAR antagonist, showed significant testicular degeneration and reversible infertility in mice. The search for RARα-specific antagonists led to the development of YCT-529, a potent and selective RARα antagonist with favorable pharmacokinetics. YCT-529 demonstrated excellent in vivo efficacy in inhibiting spermatogenesis and inducing infertility in mice, with fertility recovery following drug discontinuation. YCT-529 is now in clinical development as a candidate for male contraception.

Keywords: Vitamin A; antagonist; male contraception; reversibility; spermatogenesis inhibition.

Publication types

Review