Novel Inhibitors of Nuclear Receptor Function

描述：（由申请人提供）本项目的广泛、长期目标 建议是开发新的抑制剂，专门防止 核受体与其共激活蛋白的相互作用， NR盒结合位点，从而功能性地阻断转录激活， 核受体本提案的具体目的是：1）使用 构象受限的肽抑制剂的相互作用， 甲状腺受体（hTRf 3 1）与糖皮质激素受体相互作用蛋白 1（GRIP 1），以评估个体的结构-活性关系 GRIP 1的LXXLL三联体（NR盒）的亮氨酸侧链; 2）设计和 合成模拟侧链呈递的非肽化合物组 为了建立用于发现文库的可行支架， 以正确几何形状呈现其侧链的合成; 3） 合成非肽抑制剂文库并筛选它们以发现 核受体辅激活因子相互作用的特异性抑制剂; 4）扩大 考虑中的生化模型系统包括雌激素 受体（ER）、雄激素受体（AR）和过氧化物酶体增殖物激活的 受体（PPAR），从而允许研究抑制的特异性， 核受体辅激活剂相互作用;和5）优化任何活性 核受体功能的抑制剂，用于最大效力对抗特定的 受体和受体之间的选择性。这与健康的关系 该项目是抑制核受体功能的新方法， 为核受体介导的疾病提供新疗法的潜力 包括癌症、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。的 研究设计是利用分子设计和组合化学， 开发非肽类抑制剂。使用的方法是化学合成， 生物化学筛选、结构测定、分子设计和细胞 生理效应的生物学评价。

DESCRIPTION: (Provided by Applicant) The broad, long-term objectives of this proposal are the development of novel inhibitors that specifically prevent the interaction of nuclear receptors with their coactivating proteins through their NR box binding site and thus functionally block transcriptional activation by nuclear receptors. The Specific Aims of this proposal are 1) To use conformationally constrained peptide inhibitors of the interaction of the human thyroid receptor (hTRf3 1) with the glucocorticoid receptor interacting protein 1 (GRIP 1) to evaluate the structure-activity relationships of the individual leucine side chains of the LXXLL triad (NR box) of GRIP 1; 2) to design and synthesize sets of non-peptide compounds that mimic the side chain presentation of the LXXLL triad in order to establish viable scaffolds for discovery library synthesis that present their side chains in the correct geometry; 3) to synthesize libraries of non-peptide inhibitors and screen these to find specific inhibitors for nuclear receptor coactivator interactions; 4) to expand the biochemical model systems under consideration to include the estrogen receptor (ER), androgen receptor (AR), and peroxisome proliferator-activated receptor (PPAR) thus allowing the study of the specificity of inhibition of the nuclear receptor coactivator interactions; and 5) to optimize any active inhibitors of nuclear receptor function for maximal potency against particular receptors and selectivity among receptors. 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 cancer, cardiovascular disease, diabetes, and osteoporosis - diseases currently treated with drugs based upon hormone structure. The research design is the use of molecular design and combinatorial chemistry to develop non-peptide inhibitors. The methods to be used are chemical synthesis, biochemical screening, structure determination, molecular design, and cellular biology evaluation of physiological effect.