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. PMID: 22901802 Funding information This work was supported by: Wellcome Trust, United Kingdom Grant ID: 092809 Wellcome Trust, United Kingdom Grant ID: 095751/Z/11/Z NICHD NIH HHS, United States Grant ID: U54-HD28934 NICHD NIH HHS, United States Grant ID: U54 HD028934 NICHD NIH HHS, United States Grant ID: U01 HD060496 NCI NIH HHS, United States Grant ID: K08 CA128972 NCI NIH HHS, United States Grant ID: K08CA128972 NICHD NIH HHS, United States Grant ID: U01-HD060496 More Less keyboard_arrow_down
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