Small-molecule inhibition of BRDT for male contraception.
Bottom Line: 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.Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4.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.
Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. firstname.lastname@example.orgShow MeSH
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Mentions: To test the ability of JQ1 to reach its contraceptive target cells, the testicular bioavailability of JQ1 was assessed by serum and tissue pharmacokinetic analysis. Following a single intraperitoneal (i.p.) dose of JQ1 (50 mg/kg) in male mice, measurements of JQ1 concentration were made in serum, testis, and brain (Figure 3A and Table S3). Overall, JQ1 exhibits excellent testicular bioavailability (AUCtestis/AUCplasma = 259%), suggesting preferential distribution into this tissue compartment with rapid (Tmax = 0.25 hr) and pronounced exposure (Cmax = 34 μg/ml). Corroborating barrier permeability by JQ1, nearly uniform blood-brain barrier permeability was observed after single-dose pharmacokinetic studies (AUCbrain/AUCplasma = 98%).
Affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. email@example.com