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Small molecules targeting hepatic glucose production and insulin resistance

针对肝葡萄糖生成和胰岛素抵抗的小分子

基本信息

批准号：
10357876
负责人：
Patrick Robert Griffin
金额：
$ 65.62万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-21 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357876
关键词：
Acetylation Adrenergic Agents Affinity Antidiabetic Drugs Applications Grants Binding Biological Assay Blindness Blood Chemical Analysis Blood Glucose Canis familiaris Cardiotoxicity Cells Chemical Structure Chemicals Chronic Closure by clamp Complex Coupled Data Defect Deuterium Diabetic mouse Disease Disease Management Dose Drug Kinetics Epidemic Epigenetic Process Equilibrium Experimental Designs Formulation G-Protein-Coupled Receptors Gene Expression Genetic Genetic Transcription Glucagon Gluconeogenesis Goals Hepatic Hepatocyte High Fat Diet Histones Hormones Hydrogen Hyperglycemia In Vitro Insulin Insulin Resistance Investigation Ion Channel Kidney Diseases Lead Legal patent Liver Lysine Mass Spectrum Analysis Measurement Measures Medical Metabolic Metabolic Pathway Metformin Microsomes Mission Modeling Molecular Target Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase Phosphotransferases Play Property Proteins Proteome Pyruvate Rattus Role Safety Series Signal Transduction Solubility Specificity Structure-Activity Relationship Symptoms Testing Therapeutic Therapeutic Intervention Time Toxic effect Toxicology Transcription Coactivator Transferase Validation analog base blood glucose regulation blood lipid design diabetes management diabetic dietary drug candidate drug metabolism experimental study glucose output glucose production improved in vivo insulin secretagogues insulin sensitivity interest limb loss liver function metabolic abnormality assessment micronucleus mouse model new therapeutic target novel pre-clinical preclinical safety programs promoter safety study scaffold small molecule success targeted treatment transcription factor

项目摘要

Abstract Type 2 diabetes (T2D), particularly associated with obesity, is an epidemic in the US and worldwide and it is the leading cause of renal diseases, non-traumatic loss of limb and blindness. Despite the fact that there are current antidiabetic drugs, such as insulin secretagogues and metformin, used in the treatment of T2D, there is an urgent medical need of additional targeted therapies for an improved management of this disease in patients in which these current drugs have moderate efficacy. As T2D progresses, there is exacerbated and uncontrolled hepatic glucose production that strongly contributes to chronic hyperglycemia, a major cause of the various diabetic pathologies. Acetylation of the transcriptional coactivator PGC-1α selectively suppresses hepatic glucose production and ameliorates T2D. We have used a series of chemical high throughput and secondary assays to identify a small molecule, SR-18292, that increases PGC-1α acetylation, suppressing its gluconeogenic activity. SR-18292 inhibits glucagon and PGC-1α-dependent gluconeogenic gene expression through increased binding between PGC-1α and the GCN5 Acetyl Transferase, displacing the transcription factor HNF4α from gluconeogenic promoters and reducing epigenetic histone activation marks. In diabetic mice, SR-18292 decreases hepatic glucose output, hyperglycemia and increases liver insulin sensitivity. Combined, these studies support targeting this pathway for potential therapeutic intervention for T2D. Thus, the primary goal of this application is to characterize SR-18292 and optimize analogs that could have the potential to become a new anti-diabetic drug therapy in T2D. We will perform a complete SAR (structure and activity relationship), DMPK (drug metabolism and pharmacokinetics), toxicity and a series of in vitro and in vivo metabolic studies to validate the pathway and to identify a SR-18292 analog with robust anti-diabetic activities. The experimental design is focused on two aims: 1) SAR and DMPK studies based on the SR-18292 molecule scaffold using in-vitro and in-vivo assays and target identification (Specific Aim 1) and, 2) toxicology and in-vivo metabolic studies using the SR-18292 analog (Specific Aim 2). The outcomes of this proposal will provide significant contribution to the early-stage preclinical validation for the SR-18292 analogs as therapeutic leads for management of T2D and insulin resistance.

摘要