Small-Molecule Inhibition of BRDT for Male Contraception

TLDR

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. The study aimed to evaluate the spermatogenic effects of JQ1, a selective small‑molecule inhibitor of BET proteins. Biochemical and crystallographic studies showed that JQ1 occupies the BRDT acetyl‑lysine pocket, blocking recognition of acetylated histone H4. In mice, JQ1 reduced testis size, seminiferous tubule area, sperm count and motility, caused reversible infertility without altering hormone levels, establishing a potent, reversible contraceptive.

Abstract

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.