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：
8692994
负责人：
JAMES E BRADNER
金额：
$ 23.65万
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/8692994
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 Cloud Computing 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上的长期挑战。最近的我们实验室的研究为BRDT提供了药理目标验证男性生育能力在减数分裂性孢子虫中表达。使用针对第一个的化学工具（JQ1） BRDT的溴化域，我们已经证明了男性生育能力小分子的可行性通过靶向男性生殖细胞。由布拉德纳实验室（Bradner Laboratory）开发为抗癌剂 BRD4，一种与进化相关的蛋白质和新兴的血液恶性肿瘤依赖性，JQ1 缺乏适合男性避孕剂的选择性和类似药物的特性。因此，我们提出针对化学优化，生化表征，机械研究和临床的研究 BRDT抑制剂的翻译。使用有关分子识别的结构功能见解天然配体（含有肽的乙酰赖氨酸）和第一类的人类溴化域蛋白我们的实验室开发的溴化域抑制剂，我们建议开发BRDT的重点图书馆使用合成和生化测试的迭代循环的抑制剂。化学将使用三个在这项研究中避免相互依赖性的不同化学支架。为了支持这项研究，我们有为所有BET溴结构域蛋白提供了强大的微型生化测定。超越铅优化，将进一步优化BRDT的同质测定法在布拉德纳实验室和化学与细胞生物学研究所内，以最大化机会发现选择性的化学型。基于成功的药物开发项目我们的小组，我们组织了一个项目管理计划，数据共享计划和一个受密码保护的公共云计算站点，以确保满足化学和生物学中的可交付成果，并且数据是实时提供给调查人员的合作。预先建立的标准已经建立了BRDT的化学探针，从而指导我们的研究。铅化合物将在 MATZUK实验室内的精子发生的一系列机械研究。作为临床这项研究的目的是提供原型的治疗性BRDT抑制剂，先进的铅化合物将研究体外和体内的幻象学特性。预计治疗剂将出现从这项研究促使人类的临床研究。