Selective inhibition of BRDT for male contraception

男性避孕的药理学方法在医学上仍然是一个长期的挑战。近期 我们实验室的研究已经为BRDT提供了药理靶点验证，它是一种 雄性可育性表现在减数分裂的Spemriatonia上。使用化学工具(JQ1)以第一个为目标 BrdT的溴域，我们论证了小分子调控雄性生育的可行性。 通过瞄准雄性生殖细胞。由布拉德纳实验室开发，作为靶向抗癌药物 BRD4，一种进化相关的蛋白，在血液系统恶性肿瘤中出现癌症依赖性，JQ1 缺乏适合男性避孕药的选择性和类药物特性。因此，我们建议 化学优化、生化特性、机理研究及临床应用 BRDT抑制剂的翻译。使用关于分子识别的结构-功能洞察 天然配体(含乙酰赖氨酸的多肽)和一流的人溴结构域蛋白 本实验室开发的溴域抑制剂，我们建议建立BRDT的焦点文库 使用迭代循环进行抑制剂的合成和生化检测。化学将继续使用三个 不同的化学支架，以避免本研究中的相互依赖。为了支持这项研究，我们有 开发了适用于所有BET溴域蛋白的可靠、小型化的生化分析方法。超越铅 优化，BRDT的均相检测方法将进一步优化，以实现高通量筛选 在布拉德纳实验室和化学和细胞生物学研究所内，最大限度地利用 发现具有选择性的化学类型。基于成功完成的药物开发项目 我们组织了一个项目管理计划、一个数据共享计划和一个受密码保护的 公共云计算站点，以确保化学和生物方面的可交付成果得到满足，并且数据符合 实时提供给合作调查人员。预先建立的标准，用于一种 已经建立了BRDT的化学探针，指导了我们的研究。铅化合物的研究将在一个 Matzuk实验室内的一系列活体精子发生机制研究。作为临床上 这项研究的目的是提供一种治疗BRDT的原型抑制剂，先进的先导化合物将 在体外和体内进行表象特性的研究。预计治疗药物将会出现 从这项研究，促使人类进行临床研究。

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.