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Small-Molecule Inhibition of BRDT for Male Contraception |
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| Authors: | Martin M Matzuk Michael R McKeown Panagis Filippakopoulos Qinglei Li Lang Ma Julio E Agno Madeleine E Lemieux Sarah Picaud Richard N Yu Jun Qi Stefan Knapp James E Bradner |
| Institution: | 1 Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA 2 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA 4 Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA 5 Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA 6 Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030, USA 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA 8 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK 9 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA 10 Bioinfo, Ottawa, Ontario K1J 8G4, Canada 11 Department of Urology, Children’s Hospital Boston, Boston, MA 02115, USA 12 Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine and Health Sciences, Washington, DC 20037, USA 13 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA |
| 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. PAPERCLIP: |
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