Small-Molecule Inhibition of BRDT for Male Contraception

被引：338

作者：

Matzuk, Martin M. ^{[1
,2
,3
,4
,5
,6
]}

McKeown, Michael R. ^{[7
]}

Filippakopoulos, Panagis ^{[8
]}

Li, Qinglei ^{[9
]}

Ma, Lang ^{[1
]}

Agno, Julio E. ^{[1
]}

Lemieux, Madeleine E. ^{[7
,10
]}

Picaud, Sarah ^{[8
]}

Yu, Richard N. ^{[11
]}

Qi, Jun ^{[7
]}

Knapp, Stefan ^{[8
,12
]}

Bradner, James E. ^{[7
,13
]}

机构：

[1] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA

[5] Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA

[6] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA

[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[8] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England

[9] Texas A&M Univ, Dept Vet Integrat Biosci, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA

[10] Bioinfo, Ottawa, ON K1J 8G4, Canada

[11] Childrens Hosp, Dept Urol, Boston, MA 02115 USA

[12] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA

[13] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

来源：

CELL | 2012年 / 150卷 / 04期

基金：

英国惠康基金; 加拿大创新基金会;

关键词：

BET BROMODOMAINS; 1ST BROMODOMAIN; BINDING; TESTIS; MYC; DIFFERENTIATION; IDENTIFICATION; INFERTILITY; EXPRESSION; CHROMATIN;

D O I：

10.1016/j.cell.2012.06.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：673 / 684

页数：12

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