Discovery and Development of Antidiabetic Drugs

抗糖尿病药物的发现和开发

• 批准号: 7111942
• 负责人: GERARD M HOUSEY
• 金额: $ 47.63万
• 依托单位: HOUSEY PHARMACEUTICAL RESEARCH LAB
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111942
• 关键词: adipocytes; biological signal transduction; cell line; chemical structure function; drug discovery /isolation; genetically modified animals; high throughput technology; insulin dependent diabetes mellitus; insulin receptor; insulin sensitivity /resistance; laboratory mouse; pancreatic islet function

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.

描述（由申请人提供）：这是一份名为“发现和开发抗糖尿病药物”的ii期申请。目标是鉴定促进胰岛素/IGF信号系统irs2分支的新分子实体。NIH的支持将用于鉴定在测试细胞中促进IRS2信号传导的化合物。髓样细胞将作为高通量筛选的测试细胞；这些细胞在组织培养中的存活是实验的终点。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上得到验证。由于糖尿病是一种流行的主要慢性疾病，HPRL开发的药品将有机会在世界范围内进行临床试验。胰岛素信号失调是一个复杂的分子问题，与各种代谢性疾病有关，仅在美国就有超过1600万人发展为糖尿病。近年来开展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细胞胰岛素信号网络的重要组成部分。新的化学实体的鉴定可以增强IRS2的功能，这可能会从根本上改善2型糖尿病的治疗或预防。在第一阶段，我们获得了Joslin糖尿病中心的许可，使用专利技术来完成拟议的项目。此外，我们还确定了一个超过100,000种高复杂性和低毒性化合物的化学文库，用于高通量筛选。最后，我们建立了一个原型自动化高通量基于细胞的筛选来识别促进IRS2信号传导的化合物。这个第二阶段的SBIR应用主要集中在三个具体目标上：使用经过验证的HTP 32Dlrs2细胞检测来鉴定促进IRS2信号传导的化合物。2. 验证鉴定的化合物对IRS2信号级联的选择性和特异性。3. 在2型糖尿病转基因小鼠模型衍生的细胞系中，以及在脂肪细胞的细胞代谢试验中，建立验证化合物作为NME的生理功能，促进IRS2信号传导。从这个第二阶段的提议中出现的NME可以提供一类新的化合物来调节IRS2支架上的蛋白质-蛋白质相互作用。其中一些NME可能显示出促进中枢和外周胰岛素作用和胰腺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病比例的主要慢性疾病，该2期奖项确定的经过验证的化合物可能具有全球市场潜力。