Identification of Novel Small Molecule AMPK Modulators

新型小分子 AMPK 调节剂的鉴定

• 批准号: 8781765
• 负责人: Dave Musso
• 金额: $ 29.74万
• 依托单位: CURL BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781765
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; 5' -AMP-activated protein kinase; Adult; Adverse effects; Affinity; American; Animal Testing; Animals; Binding; Biological; Biological Assay; Biological Factors; Catalytic Domain; Cell Culture Techniques; Cells; Cellular Stress; Chemicals; Clinical; Compound 32; Computer Simulation; Consumption; Deoxyglucose; Detection; Diabetes Mellitus; Disease; Dose; Energy Metabolism; Epidemic; Explosion; FDA approved; Fatty Liver; Future; Generations; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Grant; Growth; Homeostasis; Inhibitory Concentration 50; Kinetics; Lead; Libraries; Licensing; Life Style; Liver diseases; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Metformin; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphorylation; Phosphotransferases; Play; Population; Positron-Emission Tomography; Protein Kinase; Protein Subunits; Protein-Serine-Threonine Kinases; Proteins; Regulation; Research; Role; Site; Stress; Structure-Activity Relationship; Therapeutic; Threonine; Western Blotting; base; cancer cell; cancer type; commercialization; cost effective; data mining; diabetic patient; glucose analog; human disease; in vivo; kinase inhibitor; liquid chromatography mass spectroscopy; novel; novel therapeutics; pre-clinical; protein complex; protein kinase modulator; public health relevance; response; scaffold; scale up; screening; sensor; small molecule; success; tool; tumor; tumor metabolism

DESCRIPTION (provided by applicant): Western life style has spurred the growth of numerous obesity related disorders including metabolic syndrome, type 2 diabetes and certain types of cancers to epidemic proportions. Maintaining cellular energy is a basic biological need mediated in part through amp-activated protein kinase (AMPK), therefore controlling cellular energy metabolism can play a role in treating metabolism related disorders. Indeed, AMPK regulation has been a proposed target of pharmaceutical companies, with no major clinical successes yet. Our proposal seeks to identify novel small molecules that interact with the regulatory fragment of AMPK, rather than the traditional approach of targeting the AMPK kinase domain. Currently available chemical probes/tool compounds for AMPK lack the selectivity for AMPK and hit numerous other kinases due to conserved ATP-binding kinase domains throughout the kinome. Our approach has the potential to deliver selective AMPK regulation through the non-canonical regulatory domain that can have clinical translational potential in the treatment of human diseases.

描述（由申请人提供）：西方生活方式刺激了许多肥胖相关疾病的增长，包括代谢综合征、2 型糖尿病和某些类型的癌症，达到流行的程度。维持细胞能量是一种基本的生物需求，部分通过amp激活蛋白激酶（AMPK）介导，因此控制细胞能量代谢可以在治疗代谢相关疾病中发挥作用。事实上，AMPK 监管一直是制药公司提出的目标，但尚未取得重大临床成功。我们的提案旨在鉴定与 AMPK 调控片段相互作用的新型小分子，而不是针对 AMPK 激酶结构域的传统方法。目前可用的 AMPK 化学探针/工具化合物缺乏对 AMPK 的选择性，并且由于整个激酶组中保守的 ATP 结合激酶结构域而击中许多其他激酶。我们的方法有可能通过非规范调控域提供选择性 AMPK 调控，从而在人类疾病的治疗中具有临床转化潜力。