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：
10581523
负责人：
Patrick Robert Griffin
金额：
$ 65.02万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581523
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 Hyperinsulinism 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 Symptoms Testing Therapeutic Therapeutic Intervention Toxic effect Toxicology Transcription Coactivator Transferase Validation analog blood glucose regulation blood lipid counterscreen design diabetes management diabetic dietary drug candidate drug metabolism euglycemia experimental study glucose output glucose production improved in vivo insulin secretagogues insulin sensitivity interest limb loss liver function metabolic abnormality assessment micronucleus mouse model novel novel therapeutics 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)，特别是与肥胖相关的糖尿病，在美国和全世界都是一种流行病，并且尽管事实上存在肾脏疾病、非创伤性肢体丧失和失明的主要原因。目前用于治疗T2D的抗糖尿病药物，如胰岛素促分泌剂和二甲双胍，有迫切需要额外的靶向治疗来改善这种疾病的管理对于目前这些药物具有中等疗效的患者，随着 T2D 的进展，病情会加剧。不受控制的肝葡萄糖生成强烈导致慢性高血糖，这是慢性高血糖的主要原因转录共激活因子 PGC-1α 的乙酰化可选择性抑制多种糖尿病病理。我们使用了一系列化学高通量和改善肝葡萄糖生产和改善 T2D。二次检测鉴定了一种小分子 SR-18292，该分子可增加 PGC-1α 乙酰化，抑制其 SR-18292 抑制胰高血糖素和 PGC-1α 依赖性糖异生基因表达。通过增加 PGC-1α 和 GCN5 乙酰转移酶之间的结合，取代转录糖异生启动子中的 HNF4α 因子并减少糖尿病中的表观遗传组蛋白激活标记。在小鼠中，SR-18292 降低肝脏葡萄糖输出、高血糖并增加肝脏胰岛素敏感性。综合起来，这些研究支持针对这一途径对 T2D 进行潜在的治疗干预。该应用的主要目标是表征 SR-18292 并优化可能具有以下特性的类似物：成为 T2D 抗糖尿病新药物疗法的潜力我们将进行完整的 SAR（结构和分析）。活性关系）、DMPK（药物代谢和药代动力学）、毒性等一系列体外和体内试验体内代谢研究，以验证该途径并鉴定具有强大抗糖尿病作用的 SR-18292 类似物实验设计侧重于两个目标：1）基于 SR-18292 的 SAR 和 DMPK 研究。使用体外和体内测定和靶点识别的分子支架（具体目标 1）和 2）毒理学以及使用 SR-18292 类似物的体内代谢研究（具体目标 2）。为 SR-18292 类似物治疗的早期临床前验证做出重大贡献领导 T2D 和胰岛素抵抗的管理。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production.

胰高血糖素诱导的葡萄糖产生抑制剂 SR18292 (16) 的结构-活性关系和生物学研究。

DOI：
发表时间：
2021-01-28
期刊：
影响因子：
7.3
作者：
Lin, Hua;Sharabi, Kfir;Lin, Li;Ruiz, Claudia;Zhu, Di;Cameron, Michael D;Novick, Scott J;Griffin, Patrick R;Puigserver, Pere;Kamenecka, Theodore M
通讯作者：
Kamenecka, Theodore M