Therapeutic Target for Atherogenic & Metabolic Syndromes

描述（由申请人提供）：该项目的中心目标是鉴定孤儿核受体rorα (NR1F1)的有效和特异性小分子配体。作为药物靶点，rorα具有解决糖尿病前期代谢综合征和动脉粥样硬化病理因素的潜力。rorα具有核受体典型的配体结合袋，但尚未发现具有药理活性的小分子配体。rorα纯合子失活的小鼠具有复杂的表型，包括对缺血的过度反应，对饮食诱导的动脉粥样硬化的易感性增加，以及能量代谢的改变。在分子水平上，rorα受缺氧的强烈诱导，可以抑制血管平滑肌细胞中的炎症标志物，与其在动脉粥样硬化中的作用一致。在动物疾病模型中测试有效和特定的化合物是确定其治疗潜力的关键下一步。我们建议(i)筛选一个20,000个化合物的集中文库，在一个最佳的，基于细胞的转录活性测定；（ii）开发一种结合分析，以排除假阳性并确认命中；（iii）鉴定一系列相关的活性化合物，进一步证实RORalpha作为药物开发靶点的可行性。核受体在新药开发中具有很高的成功率。这些i期研究将为选择、设计和合成配体提供基础，以表征rorα作为代谢性疾病和动脉粥样硬化模型中的药物靶点。

DESCRIPTION (provided by applicant): The central goal of this project is to identify potent and specific small molecule ligands to the orphan nuclear receptor RORalpha (NR1F1). As a drug target, RORalpha has the potential to address pathological factors in the pre-diabetic metabolic syndrome and in atherosclerosis. RORalpha has a ligand-binding pocket typical of nuclear receptors, but pharmacologically active small molecule ligands have not been identified as yet. Mice with a homozygous inactivation of RORalpha have a complex phenotype that includes an exaggerated response to ischemia, increased susceptibility to diet-induced atherosclerosis, and altered energy metabolism. At the molecular level, RORalpha is sharply induced by hypoxia and can suppress inflammatory markers in vascular smooth muscle cells, consistent with its role in atherogenesis. Testing of potent and specific compounds in animal models of disease is a critical next step in defining its therapeutic potential. We propose (i) to screen a focused library of 20,000 compounds in an optimal, cell based assay of transcriptional activity; (ii) develop a binding assay to exclude false positives and confirm hits; and (iii) identify a series of related, active compounds to further substantiate the viability of RORalpha as a target for drug development. Nuclear receptors have a very high success rate for development of new categories of drug. These Phase 1 studies will provide the foundation for the selection, design and synthesis of ligands to characterize RORalpha as a drug target in models of metabolic disease and atherosclerosis.