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Cell. 2012 Aug 17;150(4):673-84.

Small-molecule inhibition of BRDT for male contraception.

Author information

  • 1Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. mmatzuk@bcm.edu

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

Comment in

PMID:
22901802
[PubMed - indexed for MEDLINE]
PMCID:
PMC3420011
Free PMC Article

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