Targeting BRDT (testis-specific bromodomain) for Male Contraception

针对男性避孕的 BRDT（睾丸特异性溴结构域）

• 批准号: 9414228
• 负责人: Jun QI
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9414228
• 关键词: Adverse effects; Behavioral Research; Binding; Biochemical; Biological; Biological Assay; Biology; Bioluminescence; Bromodomain; Cell Line; Cells; Cellular biology; Chemicals; Chromatin; Clinical; Clinical Trials; Contraceptive Agents; DNA Modification Methylases; Development; Developmental Biology; Dose; Drug Design; Drug Kinetics; Energy Transfer; Epigenetic Process; Evaluation; Exhibits; FDA approved; Family; Fertility; Genetic study; Germ Cells; Goals; Human; In Vitro; Investigation; Laboratories; Lead; Ligands; Lysine; Male Contraceptive Agents; Male Sterility; Medicine; Morphology; Mus; Partner in relationship; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; Property; Proteins; Reader; Regulator Genes; Research; Shapes; Spermatogenesis; Spermatogenic Cell; Spermiogenesis; Sterility; Structure; Testing; Testis; Therapeutic Agents; Time; Toxic effect; base; biophysical analysis; clinical investigation; clinical translation; comparative; design; drug development; drug discovery; experimental study; genetic regulatory protein; improved; in vitro testing; in vivo; inhibitor/antagonist; insight; male; member; mimetics; molecular recognition; mouse model; novel; novel strategies; pre-clinical; research and development; research clinical testing; small molecule; small molecule inhibitor; therapeutic development; therapeutic target

PROJECT SUMMARY A pharmacologic approach for male contraception remains a longstanding challenge in medicine. Recent research from our laboratories has shown that the small-molecule inhibitor JQ1 of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins is a potent inhibitor of BRDT and that the observed contraceptive effect of JQ1 is completely reversible. However, JQ1 is a pan-BET inhibitor and therefore selective BRDT inhibitors are needed that can act as safe, effective, and reversible non-hormonal male contraceptive therapeutic agents. We thus propose research directed at the discovery, optimization, biochemical characterization, mechanistic understanding, in vivo evaluation of contraceptive effect reversibility, and clinical translation of BRDT inhibitors. In Specific Aim 1, we propose four chemical platforms to discover BRDT-selective bromodomain inhibitors for male contraception: 1) novel non-obvious mimetics of acetyl-lysine; 2) inhibitors that specifically target a unique residue in human BRDT; 3) unique ligands that can bind selectivly to both bromodomains of BRDT; and 4) bifunctional small molecules designed to direct selective degradation of the BRDT protein. Structure-based drug design, biochemical, and biophysical studies will be used to drive selectivity improvements. For Specific Aim 2, the selective BDRT inhibitors identified from Specific Aim 1 will be further optimized for cellular potency and selectivity for BRDT through an iterative process that will also involve in vitro testing for ADMET properties. Specific Aim 3 will explore the clinical potential of the inhibitors through in vivo pharmacokinetic studies and pre-clinical evaluation for male contraception, involving definitive studies of spermatogenesis, fertility, and reversibility in male mice.

项目摘要 男性避孕的药理学方法仍然是医学界长期面临的挑战。最近 我们实验室的研究表明，布罗莫结构域的小分子抑制剂JQ 1和 表观遗传阅读器蛋白的末端外（BET）亚家族是BRDT的有效抑制剂，并且观察到 JQ 1的避孕作用是完全可逆的。然而，JQ 1是泛BET抑制剂，因此具有选择性。 需要BRDT抑制剂作为安全，有效和可逆的非激素男性避孕药 治疗剂。因此，我们建议研究针对发现，优化，生化 表征、机制理解、避孕效果可逆性的体内评价和临床 BRDT抑制剂的翻译。在具体目标1中，我们提出了四个化学平台来发现BRDT选择性 用于男性避孕的布罗莫结构域抑制剂：1）乙酰赖氨酸的新的非明显模拟物; 2） 特异性靶向人BRDT中独特残基; 3）可选择性结合人BRDT和人BRDT中的独特配体 BRDT的溴结构域;和4）双功能小分子，其被设计为直接选择性降解BRDT的溴结构域。 BRDT蛋白。基于结构的药物设计，生物化学和生物物理学研究将用于驱动选择性 改进.对于特定目标2，将进一步研究从特定目标1鉴定的选择性BDRT抑制剂。 通过迭代过程优化BRDT的细胞效能和选择性， 测试ADMET属性。具体目标3将通过体内试验探索抑制剂的临床潜力 男性避孕药的药代动力学研究和临床前评价，包括以下方面的确定性研究： 雄性小鼠的精子发生、生育力和可逆性。