Selective inhibition of BRDT for male contraception

选择性抑制 BRDT 用于男性避孕

基本信息

批准号：
8549777
负责人：
JAMES E BRADNER
金额：
$ 23.09万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
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/8549777
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 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 screening small molecule therapeutic target tool translational study

项目摘要

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。最近的我们实验室的研究为 BRDT 提供了药理靶点验证，BRDT 是雄性生育力以减数分裂精原细胞表达。使用针对第一个目标的化学工具（JQ1） BRDT的溴结构域，我们证明了小分子调节男性生育力的可行性通过针对雄性生殖细胞。由 Bradner 实验室开发，作为靶向抗癌剂 BRD4，一种进化相关蛋白和血液系统恶性肿瘤中新出现的癌症依赖性，JQ1 缺乏适合男性避孕药的选择性和类似药物的特性。因此我们建议研究方向为化学优化、生化表征、机理研究和临床 BRDT抑制剂的翻译。利用有关分子识别的结构-功能见解天然配体（含有乙酰基赖氨酸的肽）和一流的人类溴结构域蛋白我们实验室开发的 bromodomain 抑制剂，我们建议开发 BRDT 的重点库使用合成和生化测试的迭代循环来抑制抑制剂。化学将使用三个进行不同的化学支架，以避免本研究中的相互依赖性。为了支持这项研究，我们有开发了针对所有 BET 溴结构域蛋白的稳健、小型生化检测。超越铅优化，BRDT均相检测将进一步优化以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内，最大限度地利用机会发现赋予选择性的化学型。基于成功完成的药物开发项目我们的团队组织了项目管理计划、数据共享计划和密码保护计划公共云计算站点，以确保满足化学和生物学的可交付成果，并且数据实时提供给合作研究人员。预先设定的特征标准 BRDT化学探针的建立，指导了我们的研究。先导化合物将在 Matzuk 实验室对体内精子发生进行了一系列机制研究。作为临床这项研究的目标是提供一种原型治疗性 BRDT 抑制剂，先进的先导化合物将进行体外和体内药理学特性研究。预计治疗药物将会出现这项研究促进了人体临床研究。