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）

基本信息

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
项目类别：
财政年份：
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

项目摘要

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上的长期挑战。最近的我们实验室的研究表明，溴结构域的小分子抑制剂JQ1和表观遗传学读蛋白的外部（BET）亚科是BRDT的有效抑制剂，观察到 JQ1的避孕作用是完全可逆的。但是，JQ1是一种泛膏抑制剂，因此有选择性需要BRDT抑制剂，以便起作用，可作为安全，有效和可逆的非荷尔蒙男性避孕药治疗剂。因此，我们提出了针对发现，优化，生化的研究表征，机械理解，体内评估避孕效应可逆性和临床 BRDT抑制剂的翻译。在特定目标1中，我们提出了四个化学平台，以发现BRDT选择性雄性避孕剂的溴结构域抑制剂：1）乙酰赖氨酸的新型非明显副词； 2）抑制剂特别针对人类BRDT中的独特残留物； 3）独特的配体，可以选择与两者选择结合 BRDT的溴化群； 4）双功能的小分子，旨在导致选择性降解 BRDT蛋白。基于结构的药物设计，生化和生物物理研究将用于推动选择性改进。对于特定目标2，从特定目标1中鉴定的选择性BDRT抑制剂将进一步通过迭代过程优化了BRDT的细胞效力和选择性，该过程也将涉及体外测试ADMET属性。特定的目标3将通过体内探索抑制剂的临床潜力药代动力学研究和临床前评估男性避孕，涉及对雄性小鼠的精子发生，生育能力和可逆性。