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.

抽象的 2型糖尿病（T2D），尤其是与肥胖有关的糖尿病，在美国和全球是一种流行病肾脏疾病的主要原因，肢体和失明的非创伤丧失。尽管有当前用于治疗T2D的胰岛素促分子和二甲双胍等当前抗糖尿病药物紧急医疗需要其他针对性疗法，以改善这种疾病的治疗这些当前药物具有中等效率的患者。随着T2D的进展，发生了加重的不受控制的肝葡萄糖产生强烈有助于慢性高血糖，这是造成的主要原因各种糖尿病病理。转录共激活因子PGC-1α的乙酰化选择性抑制肝葡萄糖产生并改善T2D。我们使用了一系列化学高通量和鉴定小分子SR-18292的次要测定，该分子增加了PGC-1α乙酰化，从而抑制了其糖原活性。 SR-18292抑制胰高血糖素和PGC-1α依赖性糖生成基因表达通过增加PGC-1α和GCN5乙酰基转移酶之间的结合，取代转录谷杆菌发起启动子的HNF4α因子和降低表观遗传组蛋白激活标记。在糖尿病中小鼠SR-18292降低了肝葡萄糖输出，高血糖并增加了肝胰岛素敏感性。这些研究结合在一起，支持针对T2D潜在治疗干预途径的这一途径。那，该应用程序的主要目标是表征SR-18292并优化可能具有的类似物在T2D中成为一种新的抗糖尿病药物疗法的潜力。我们将执行完整的SAR（结构和活动关系），DMPK（药物代谢和药代动力学），毒性以及一系列体外和体内代谢研究以验证途径并鉴定具有强大抗糖尿病的SR-18292类似物活动。实验设计的重点是两个目标：1）基于SR-18292的SAR和DMPK研究使用体外和体内测定和靶标识别（特定目标1）和2）毒理学的分子支架使用SR-18292类似物的体内代谢研究（特定目标2）。该提案的结果将为SR-18292类似物作为治疗的早期临床前验证提供了重大贡献铅用于管理T2D和胰岛素抵抗。