Small-Molecule Inhibition of BRDT for Male Contraception

• Published in: Cell 2012-08, Vol.150 (4), p.673-684
• Main Authors: Matzuk, Martin M., McKeown, Michael R., Filippakopoulos, Panagis, Li, Qinglei, Ma, Lang, Agno, Julio E., Lemieux, Madeleine E., Picaud, Sarah, Yu, Richard N., Qi, Jun, Knapp, Stefan, Bradner, James E.
• Format: Article
• Language: English
• Subjects: Animals; antifertility effect; Azepines - chemistry; Azepines - pharmacology; Blood-Testis Barrier; chromatin; contraception; Contraceptive Agents, Male - chemistry; Contraceptive Agents, Male - pharmacology; contraceptives; epigenetics; Female; histones; Humans; Male; males; medicine; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Models, Molecular; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Protein Structure, Tertiary; Sperm Count; Sperm Motility - drug effects; spermatogenesis; spermatozoa; Spermatozoa - drug effects; testes; Testis - cytology; Testis - drug effects; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.06.045

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. [Display omitted] [Display omitted] ► Bromodomain, testis-specific (BRDT) is a contraceptive target ► JQ1 is a BRDT inhibitor that causes a reversible contraceptive effect in male mice ► JQ1 alters spermatogenesis at the spermatocyte and round spermatid stages ► JQ1 treatment targets the male germline and reduces spermatozoa number and motility Inhibition of the chromatin reader protein BRDT with the small molecule JQ1 provides an approach for reversible male contraception.