Selective inhibition of BRDT for male contraception

选择性抑制 BRDT 用于男性避孕

• 批准号: 8528971
• 负责人: JAMES E BRADNER
• 金额: $ 24.33万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528971
• 关键词: Antineoplastic Agents; Binding; Bioavailable; Biochemical; Biochemistry; Biological; Biological Assay; Biology; Bromodomain; Cellular biology; Characteristics; Chemicals; Chemistry; Chromatin; Cleaved cell; Clinical; Clinical Trials; Complex; Contraceptive Agents; DNA Methyltransferase; DNA Modification Methylases; Data; Dependency; Development; Developmental Biology; Dose; Epigenetic Process; Exhibits; Family; Fertility; Genes; Germ Cells; Goals; Hematologic Neoplasms; Human; In Vitro; Institutes; Investigation; Knowledge; Laboratories; Lead; Libraries; Ligands; Lysine; Male Contraceptions; Male Contraceptive Agents; Malignant Neoplasms; Medicine; Meiosis; Modeling; Mus; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Property; Protein Binding; Proteins; Public Health; Reader; Reproductive Biology; Research; Research Personnel; Research Support; Rodent; Screening procedure; Series; Shapes; Site; Sperm Count Procedure; Spermatocytes; Spermatogenesis; Spermatogenic Cell; Spermiogenesis; Structure; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Translations; Validation; Work; base; cell motility; comparative; contraceptive target; data sharing; drug development; genetic regulatory protein; high throughput screening; in vivo; inhibitor/antagonist; insight; male; meetings; mimetics; miniaturize; molecular recognition; novel; pharmacophore; pill; prototype; research study; scaffold; small molecule; therapeutic target; tool; translational study

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Recent research from our laboratories has provided pharmacologic target validation for BRDT, a detemiinant of male fertility expressed in meiotic spemriatogonia. Using a chemical tool (JQ1) which targets the first bromodomain of BRDT, we have demonstrated the feasibility of small-molecule modulation of male fertility by targeting the male germ cell. Developed by the Bradner laboratory as an anti-cancer agent targeting BRD4, an evolutionarily related protein and emerging cancer dependency in hematologic malignancies, JQ1 lacks the selectivity and drug-like properties befitting a male contraceptive agent. We therefore propose research directed at the chemical optimization, biochemical characterization, mechanistic study and clinical translation of BRDT inhibitors. Using structure-function insights regarding the molecular recognition of human bromodomain proteins by natural ligands (acetyl-lysine containing peptides) and first-in-class bromodomain inhibitors developed by our laboratory, we propose to develop focused libraries of BRDT inhibitors using iterative cycles of synthesis and biochemical testing. Chemistry will proceed using three distinct chemical scaffolds, to avoid inter-dependency in this research. To support this research, we have developed robust, miniaturized biochemical assays for all BET bromodomain proteins. Beyond lead optimization, the homogeneous assay for BRDT will be further optimized for high-throughput screening within the Bradner laboratory and Institute of Chemistry and Cellular Biology, to maximize the opportunity for discovering selectivity-conferring chemotypes. Based on successful drug development projects completed by our group, we have organized a Project Management Plan, a Data Sharing Plan and a password-protected common cloud computing site, to assure that deliverables in chemistry and biology are met, and that data is provided to collaborating investigators in real-time. Pre-established criteria for the characteristics of a chemical probe for BRDT have been established, guiding our research. Lead compounds will be studied in a series of mechanistic studies of spermatogenesis in vivo, within the Matzuk laboratory. As the clinical objective of this research is to deliver a prototype therapeutic BRDT inhibitor, advanced lead compounds will be studied for phanmacologic properties in vitro and in vivo. It is expected that therapeutic agents will emerge from this research, prompting human clinical investigation.

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 我们实验室的研究为BRDT提供了药理学靶点验证， 雄性育性在精原细胞减数分裂中表现。使用化学工具（JQ 1），其目标是第一个 BRDT的溴结构域，我们已经证明了小分子调节男性生育力的可行性 通过瞄准男性生殖细胞。由布拉德纳实验室开发，作为一种抗癌剂， BRD 4，一种进化相关的蛋白质，与恶性血液病的癌症依赖性有关，JQ 1 缺乏适合男性避孕剂的选择性和药物样性质。因此我们建议 针对化学优化、生化表征、机制研究和临床的研究 BRDT抑制剂的翻译。利用结构-功能的见解，关于分子识别的 通过天然配体（含乙酰基赖氨酸的肽）和同类第一的人布罗莫结构域蛋白 我们实验室开发的溴结构域抑制剂，我们建议开发BRDT的聚焦文库 使用合成和生化测试的迭代循环的抑制剂。化学将使用三个 不同的化学支架，以避免在这项研究中的相互依赖。为了支持这项研究，我们 开发了用于所有BET溴结构域蛋白的稳健的小型化生物化学测定。超越铅 优化，BRDT的均相测定将进一步优化用于高通量筛选 在布拉德纳实验室和化学与细胞生物学研究所，以最大限度地提高机会， 发现赋予选择性的化学型。根据成功完成的药物开发项目， 我们的团队，我们组织了一个项目管理计划，一个数据共享计划和一个密码保护的 常见的云计算站点，以确保满足化学和生物学方面的可交付成果，并且数据 实时提供给合作的研究人员。预先确定的标准， 建立了BRDT的化学探针，指导了我们的研究。铅化合物将在一个 在Matzuk实验室进行的一系列精子发生的体内机制研究。作为临床 这项研究的目的是提供一种原型治疗BRDT抑制剂，先进的先导化合物将 在体外和体内研究其形态学特性。预计治疗剂将出现 从这项研究，促进人类临床研究。