Discovery and Development of Antidiabetic Drugs

描述(申请人提供)：这是名为“抗糖尿病药物的发现和开发”的第二阶段申请。目标是确定新的分子实体，促进胰岛素/胰岛素样生长因子信号系统的IRS2分支。NIH的支持将被用来识别在测试细胞中促进IRS2信号传递的化合物。高通量筛选的试验细胞将被用作试验细胞；这些细胞在组织培养中的存活是试验终点。这些化合物促进胰腺β细胞生长、功能和存活的能力将在啮齿动物β细胞系和啮齿动物胰岛中得到验证。由于糖尿病是一种流行性的主要慢性疾病，在HPRL开发的药品将有机会在世界各地进行临床测试。胰岛素信号转导失调是一个复杂的分子问题，它与各种代谢性疾病有关，仅在美国就有1600多万人发展为糖尿病。过去几年进行的基础科学研究表明，胰岛素受体底物-2蛋白是外周组织和胰岛β细胞中胰岛素信号网络的重要组成部分。识别能够增强IRS2功能的新化学物质可能会在治疗或预防2型糖尿病方面带来根本性的改进。在第一阶段，我们获得了Joslin糖尿病中心的许可，可以使用完成拟议项目所需的专利技术。此外，我们还确定了一个超过100,000个高复杂性和低毒性的化合物文库，用于高通量筛选。最后，我们建立了一个基于细胞的自动化高通量筛选原型，以识别促进IRS2信号转导的化合物。这个第二阶段的SBIR应用集中在三个特定的目标上：1.使用经过验证的基于细胞的HTP 32Dlrs2分析来识别促进IRS2信号转导的化合物。2.验证所鉴定的化合物对IRS2信号级联的选择性和特异性。3.在转基因2型糖尿病小鼠模型衍生的细胞系中，以及在脂肪细胞的细胞代谢测试中，确定验证化合物的生理功能为促进IRS2信号转导的NME。从这一第二阶段提案中出现的NME可以提供一类新的化合物，在IRS2支架上调节蛋白质-蛋白质相互作用。其中一些NME可以显示出促进中枢和外周胰岛素作用以及胰岛β细胞功能的能力，从而可以治疗或治愈糖尿病。由于糖尿病是一种流行比例的主要慢性疾病，因此本阶段2奖确定的经过验证的化合物可能具有全球市场潜力。

DESCRIPTION (provided by applicant): This is the Phase 2 application entitled "Discovery and Development of Antidiabetic Drugs." The goal is to identify new molecular entities that promote the IRS2-branch of the insulin/IGF signaling system. The NIH support will be used to identify compounds that promote IRS2 signaling in test cells. Myloid cells will be used as the test cell for high throughput screening; survival of these cells in tissue culture is the assay endpoint. The ability of these compounds to promote pancreatic beta-cell growth, function and survival will be validated in rodent beta-cells lines and rodent islets. Since diabetes is a major chronic disease of epidemic proportions, pharmaceutical products developed at HPRL will have opportunities for clinical testing worldwide. Dysregulated insulin signaling is a complex molecular problem that is associated with various metabolic diseases that progress to diabetes in more than 16 million people in the United States alone. Basic scientific investigation conducted over the past several years reveals that the insulin receptor substrate-2 protein is an essential component of the insulin signaling network in peripheral tissues and pancreatic beta-cells. The identification of new chemical entities that enhance the function of IRS2 might lead to fundamental improvements in the treatment or prevention type 2 diabetes. During Phase 1, we obtained a license from the Joslin Diabetes Center to use patented technology required to accomplish the proposed project. Moreover, we identified a chemical library in excess of 100,000 compounds of high complexity and low toxicity for high throughput screening. Finally, we established a prototype automated high throughput cell- based screen to identify compounds that promote IRS2 signaling. This Phase 2 SBIR application is focused upon 3 Specific Aims: 1. Use the validated HTP 32Dlrs2 cell-based assay to identify compounds that promote IRS2 signaling. 2. Validate the selectivity and specificity of the identified compounds toward the IRS2 signaling cascade. 3. Establish the physiological function of the validated compounds as NME's that promote IRS2 signaling in cell lines derived from transgenic mouse models of type 2 diabetes as well as in cellular metabolic assays in adipocytes. The NME's that emerge from this Phase 2 proposal can provide a new class of compounds that modulate protein-protein interactions upon the IRS2 scaffold. Some of these NME's could display the ability to promote central and peripheral insulin action and pancreatic beta-cell function, which can treat or cure diabetes. Since diabetes is a major chronic disease of epidemic proportions, validated compounds identified by this Phase 2 Award can have a worldwide market potential.