JIP mimics for the treatment of diabetes

JIP 模拟物治疗糖尿病

基本信息

批准号：
7900908
负责人：
Maurizio Pellecchia
金额：
$ 75.17万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900908
关键词：
20 year old ATF2 gene Accounting Adipocytes Adipose tissue Adult Affect Affinity Age Binding Blindness Cause of Death Cells Cessation of life Chemicals Clinical Color Communities Consensus Sequence Data Death Certificates Death Rate Deposition Development Diabetes Mellitus Diabetic mouse Diagnosis Disease Drug Industry Embryo Event Feedback Fibroblasts Genes Genetic Goals Half-Life Heart Diseases Human Hypoglycemia IRS1 gene In Vitro Individual Inflammatory Insulin Insulin Resistance JNK-activating protein kinase JUN gene Kidney Failure Laboratories Length Liver MAPK14 gene MAPK8 gene Mediating Metabolic Diseases Modeling Monoclonal Antibody R24 Mus Muscle Fibers Mutation Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Process Property Protein Kinase Proteins Publishing Rat-1 Rattus Recombinants Regulation Reporting Research Personnel Resistance Resolution Resources Risk Role Route Scaffolding Protein Scientist Series Signal Transduction Site Skeletal Muscle Stroke Structure Substrate Domain Testing Time United States National Institutes of Health aged base chemical resource cytokine design diabetes mellitus therapy drug candidate drug development human DOK1 protein in vitro activity in vivo in vivo Model inhibitor/antagonist innovation insulin signaling interdisciplinary approach mouse model novel obesity treatment overexpression programs repository small molecule tool upstream kinase validation studies

项目摘要

DESCRIPTION (provided by applicant): Type-2 diabetes is a metabolic disorder that affects > 150 million individuals worldwide and represents the sixth highest cause of death in the U.S. in 2002. Heart disease and stroke account for about 65 percent of deaths in people with diabetes and adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes. These observations underline the devastating effects of diabetes and the urgency of providing the clinicians and the pharmaceutical industry with novel targets and clinical tools, such as specific small molecule drugs for the development of novel therapies. It is now clear that activation of the protein kinase JNK could act as an important negative feedback regulator of insulin signaling. JNK is regulated by JNK-interacting protein-1, JIP1, a scaffolding protein which enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. The JNK-JIP1 interaction is mediated by a specific peptide region on JIP1 (pepJIPI). Recent in vivo data with a cell-permeable JIP1 peptide showed that its administration in both genetically and dietary mice models of insulin resistance and type-2 diabetes restored normoglycemia without causing hypoglycemia in lean mice. Numerous laboratories around the world are using this peptide to probe the involvement of the JNK pathway in diabetes and other human disorders. We propose a highly integrated, multidisciplinary approach to derive novel, safe and efficacious drug-like JIP mimics and to test the most promising compounds in mice models of diabetes. The most promising and validated compounds will be deposited in the NIH chemical repository and made available as a resource to the entire scientific community. Relevance: Overall, the risk for death among people with diabetes is about twice that of people without diabetes of similar age, with heart disease and stroke accounting for about two thirds of deaths in people with diabetes. In addition, diabetes is the leading cause of new cases of blindness among adults aged 20 to 74 years, as well as kidney failure, accounting for 44 percent of new cases in 2002. Central to insulin regulation, the interactions between the protein kinase JNK and the scaffolding protein JIP1 activate a series of cellular events which result in altered insulin signaling. A central hypothesis in this study is that the development of compounds capable of interfering with the JNK-JIP1 interactions (JIP mimics) represents a promising, innovative, yet unexplored route to advance novel therapies against diabetes.

描述（由申请人提供）： 2型糖尿病是一种代谢性疾病，影响了全球> 1.5亿人，代表了2002年美国第六高的死亡原因。心脏病和中风约占糖尿病患者和糖尿病患者死亡的65％，心脏病死亡率比没有糖尿病的成人高2至4倍。这些观察结果强调了糖尿病的毁灭性影响以及为临床医生和制药行业提供新的靶标和临床工具的紧迫性，例如用于开发新疗法的特定小分子药物。现在很明显，蛋白激酶JNK的激活可以充当胰岛素信号传导的重要负反馈调节剂。 JNK受JNK相互作用蛋白-1，JIP1的调节，JIP1是一种脚手架蛋白，可通过在JNK和上游激酶之间产生接近效应来增强JNK信号传导。 JNK-JIP1相互作用是由JIP1（pepjipi）上的特定肽区域介导的。最近使用可渗透细胞JIP1肽的体内数据显示，其在遗传和饮食小鼠胰岛素抵抗和2型糖尿病模型中的给药恢复了正常血糖，而不会引起瘦小小鼠的低血糖。世界各地的许多实验室都使用这种肽来探测JNK途径在糖尿病和其他人类疾病中的参与。我们提出了一种高度综合的多学科方法，用于得出新颖，安全有效的类似药物样的JIP模拟物，并测试糖尿病小鼠模型中最有希望的化合物。最有前途和经过验证的化合物将存放在NIH化学存储库中，并作为资源提供给整个科学界。相关性：总体而言，糖尿病患者死亡的风险约为没有年龄相似的糖尿病的人的两倍，心脏病和中风占糖尿病患者的三分之二。此外，糖尿病是20至74岁成年人的新病例的主要原因，以及肾衰竭，占2002年的新病例的44％。胰岛素调节的中心，蛋白激酶JNK的相互作用与蛋白质激酶JNK与支架蛋白质JIP1之间的相互作用激活了一系列细胞事件，从而导致一系列细胞事件，从而导致胰岛素信号构成改变的胰岛素信号。这项研究中的一个核心假设是，能够干扰JNK-JIP1相互作用（JIP MIMICS）的化合物的发展代表了一种有希望的，创新的，但未开发的途径，可以推进针对糖尿病的新疗法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor.

DOI：
10.1021/jm200479c
发表时间：
2011-09-22
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Stebbins, John L.;De, Surya K.;Pavlickova, Petra;Chen, Vida;Machleidt, Thomas;Chen, Li-Hsing;Kuntzen, Christian;Kitada, Shinichi;Karin, Michael;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio

Design, synthesis, and structure-activity relationship studies of thiophene-3-carboxamide derivatives as dual inhibitors of the c-Jun N-terminal kinase.

DOI：
10.1016/j.bmc.2011.03.017
发表时间：
2011-04-15
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY
影响因子：
3.5
作者：
De, Surya K.;Barile, Elisa;Chen, Vida;Stebbins, John L.;Cellitti, Jason F.;Machleidt, Thomas;Carlson, Coby B.;Yang, Li;Dahl, Russell;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio

Synthesis and optimization of thiadiazole derivatives as a novel class of substrate competitive c-Jun N-terminal kinase inhibitors.

DOI：
10.1016/j.bmc.2009.12.013
发表时间：
2010-01-15
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY
影响因子：
3.5
作者：
De, Surya K.;Chen, Vida;Stebbins, John L.;Chen, Li-Hsing;Cellitti, Jason F.;Machleidt, Thomas;Barile, Elisa;Riel-Mehan, Megan;Dahl, Russell;Yang, Li;Emdadi, Aras;Murphy, Ria;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio