Discovery and Development of Antidiabetic Drugs

描述（由申请人提供）：这是标题为“发现和开发抗糖尿病药物”的2期申请。“我们的目标是确定新的分子实体，促进胰岛素/IGF信号系统的IRS 2-分支。NIH的支持将用于鉴定在测试细胞中促进IRS 2信号传导的化合物。将使用髓样细胞作为高通量筛选的试验细胞;这些细胞在组织培养物中的存活率是试验终点。将在啮齿动物β细胞系和啮齿动物胰岛中验证这些化合物促进胰腺β细胞生长、功能和存活的能力。由于糖尿病是一种流行性的主要慢性疾病，HPRL开发的药品将有机会在全球范围内进行临床试验。胰岛素信号转导失调是一个复杂的分子问题，与各种代谢疾病有关，仅在美国就有超过1600万人发展为糖尿病。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腺β细胞中胰岛素信号网络的重要组成部分。鉴定出能够增强IRS 2功能的新化学实体可能会导致治疗或预防2型糖尿病的根本改善。在第一阶段，我们获得了乔斯林糖尿病中心的许可证，可以使用完成拟议项目所需的专利技术。此外，我们鉴定了超过100，000种高复杂性和低毒性的化合物的化学文库用于高通量筛选。最后，我们建立了一个原型的自动化高通量细胞为基础的筛选，以确定化合物，促进IRS 2信号。这第二阶段SBIR应用程序集中在3个具体目标：1。使用经验证的基于HTP 32 Dlrs 2细胞的试验来鉴定促进IRS 2信号传导的化合物。2.证实了所鉴定的化合物对IRS 2信号级联的选择性和特异性。3.确立经验证的化合物作为NME的生理功能，其在源自2型糖尿病转基因小鼠模型的细胞系中以及在脂肪细胞的细胞代谢测定中促进IRS 2信号传导。从该阶段2提议中出现的NME可以提供一类新的化合物，其调节IRS 2支架上的蛋白质-蛋白质相互作用。这些NME中的一些可以显示促进中枢和外周胰岛素作用以及胰腺β细胞功能的能力，这可以治疗或治愈糖尿病。由于糖尿病是一种流行性的主要慢性疾病，因此该第2阶段奖项确定的有效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.