Document Type
Journal Article
Publication Date
8-17-2012
Journal
Cell
Volume
Volume 150, Issue4
Inclusive Pages
673-684
Keywords
Azepines--pharmacology; Contraceptive Agents; Male--pharmacology; Nuclear Proteins--antagonists & inhibitors; Triazoles--pharmacology
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
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
APA Citation
Matzuk, M. M., McKeown, M. R., Filippakopoulos, P., Li, Q., Ma, L., Agno, J. E., . . . Bradner, J. E. (2012). Small-molecule inhibition of BRDT for male contraception. Cell, 150(4), 673-684.
Peer Reviewed
1
Open Access
1
Comments
Reproduced with permission of Cell.