Novel Inhibitors of Nuclear Receptor Function

该提案的广泛的长期目标是开发新的“类药物”， 特异性阻止核受体与其共调节因子相互作用的抑制剂 蛋白质通过其NR盒结合位点，并在功能上阻断核转录激活 受体。本提案的具体目的是：1）确定哪些化学支架可以 提供辅助调节剂与甲状腺受体（TR）相互作用的小分子抑制剂， 糖皮质激素受体（GR）、雄激素受体（AR）和过氧化物酶体增殖物激活 受体y（PPARy）和哪些支架对单个受体表现出选择性; 2）了解 抑制剂功能的分子机制，通过确定活性物质的结合模式， 抑制剂和支架与单个受体的构效关系以及 受体;以及3）确定针对特定受体的作用的分子选择性 与靶向受体信号传导的功能变化和 在细胞环境中的转录调控。该项目的健康相关性在于， 抑制核受体功能的新方法有可能为以下疾病提供新的治疗方法： 由核受体介导的疾病，包括心血管疾病、糖尿病和 骨质疏松症-目前用基于激素结构的药物治疗的疾病。研究 设计是使用基于知识的结构，化学和细胞生物学来合理地生产 靶蛋白相互作用的新型小分子抑制剂。要使用的方法是高 通量筛选，平行化学，药物化学，高通量X射线 晶体学（结构基因组学），细胞生物学，基因组学和药理学，以开发 抑制剂的

The broad, long-term objectives of this proposal are the development of novel "drug-like" inhibitors that specifically prevent the interaction of nuclear receptors with their coregulating proteins through their NR box binding site and functionally block transcriptional activation by nuclear receptors. The Specific Aims of this proposal are 1) to determine which chemical scaffolds can afford small molecule inhibitors of the interaction of co-regulators with the thyroid receptor (TR), glucocorticoid receptor (GR), androgen receptor (AR) and peroxisome proliferator activated receptor y (PPARy) and which scaffolds exhibit selectivity for individual receptors; 2) to understand the molecular mechanism of inhibitor function by determining the modes of binding of active inhibitors and the structure activity relationships of scaffolds with individual receptors and among receptors; and 3) to determine how molecular selectivity of action against a particular receptor relates to functional changes in signaling by the targeted receptor and overall changes in transcriptional regulation in the cellular environment. The health relatedness of this project is that the new method of inhibiting nuclear receptor function has the potential to provide new therapies for diseases mediated by nuclear receptors which include cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of knowledge based structure, chemistry, and cell biology to rationally produce novel small molecule inhibitors of the targeted protein interaction. The methods to be used are high throughput screening, parallel chemistry, medicinal chemistry, high throughput X-ray crystallography (structural genomics), cell biology, genomics, and pharmacology to develop inhibitors.