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，影响全球超过 1.5 亿人，是 2002 年美国第六大死因。心脏病和中风约占糖尿病患者死亡的 65%，成人糖尿病患者有心脏病疾病死亡率比未患糖尿病的成年人高约 2 至 4 倍。这些观察结果强调了糖尿病的破坏性影响以及为临床医生和制药行业提供新靶点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。现在很清楚，蛋白激酶 JNK 的激活可以作为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) 调节，JIP1 是一种支架蛋白，通过在 JNK 和上游激酶之间产生邻近效应来增强 JNK 信号传导。 JNK-JIP1 相互作用由 JIP1 (pepJIPI) 上的特定肽区域介导。最近关于细胞渗透性 JIP1 肽的体内数据表明，在胰岛素抵抗和 2 型糖尿病的遗传和饮食小鼠模型中施用该肽可以恢复正常血糖，而不会引起瘦小鼠的低血糖。世界各地的许多实验室正在使用这种肽来探讨 JNK 通路在糖尿病和其他人类疾病中的作用。我们提出了一种高度集成、多学科的方法来衍生新型、安全和有效的类药 JIP 模拟物，并在糖尿病小鼠模型中测试最有前途的化合物。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，糖尿病患者的死亡风险约为同龄非糖尿病患者的两倍，心脏病和中风约占糖尿病患者死亡的三分之二。此外，糖尿病是 20 至 74 岁成年人新发失明病例和肾衰竭的主要原因，占 2002 年新发病例的 44%。蛋白激酶 JNK 和肾功能衰竭之间的相互作用是胰岛素调节的核心。支架蛋白 JIP1 激活一系列细胞事件，导致胰岛素信号传导改变。这项研究的一个中心假设是，开发能够干扰 JNK-JIP1 相互作用的化合物（JIP 模拟物）代表了一种有前途的、创新的、但尚未探索的途径，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.

一种有效的、选择性的双重 ATP 和底物竞争性亚纳摩尔二齿 c-Jun N 末端激酶 (JNK) 抑制剂的设计和表征。

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 of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.

c-Jun N 末端激酶的底物竞争性、选择性和体内活性三唑和噻二唑抑制剂的设计、合成和构效关系。

DOI：
发表时间：
2009-04-09
期刊：
影响因子：
7.3
作者：
De SK;Stebbins JL;Chen LH;Riel-Mehan M;Machleidt T;Dahl R;Yuan H;Emdadi A;Barile E;Chen V;Murphy R;Pellecchia M
通讯作者：
Pellecchia M

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

作为一类新型底物竞争性 c-Jun N 末端激酶抑制剂的噻二唑衍生物的合成和优化。

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

Identification of a new JNK inhibitor targeting the JNK-JIP interaction site.

鉴定针对 JNK-JIP 相互作用位点的新型 JNK 抑制剂。

DOI：
发表时间：
2008-10-28
期刊：
影响因子：
11.1
作者：
Stebbins, John L;De, Surya K;Machleidt, Thomas;Becattini, Barbara;Vazquez, Jesus;Kuntzen, Christian;Chen, Li;Cellitti, Jason F;Riel;Emdadi, Aras;Solinas, Giovanni;Karin, Michael;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio

Discovery of 2-(5-nitrothiazol-2-ylthio)benzo[d]thiazoles as novel c-Jun N-terminal kinase inhibitors.

发现 2-(5-硝基噻唑-2-基硫基)苯并[d]噻唑作为新型 c-Jun N 末端激酶抑制剂。

DOI：
发表时间：
2009-04-01
期刊：
影响因子：
3.5
作者：
De, Surya K;Chen, Li;Stebbins, John L;Machleidt, Thomas;Riel;Dahl, Russell;Chen, Vida;Yuan, Hongbin;Barile, Elisa;Emdadi, Aras;Murphy, Ria;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio