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

• 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
• 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

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 2型糖尿病(T2D)，特别是与肥胖有关的疾病，在美国和世界范围内是一种流行病，而且 肾脏疾病的主要原因是非外伤性肢体丧失和失明。尽管有这样一个事实 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 迫切需要更多的靶向治疗，以改善对这种疾病的管理 目前这些药物有中等疗效的患者。随着T2D的进展，会加剧和 不受控制的肝脏葡萄糖产生，强烈导致慢性高血糖，这是 各种糖尿病的病理改变。转录辅活化子pGC-1α的乙酰化选择性抑制 肝脏葡萄糖生成和改善T2D。我们已经使用了一系列的化学高通量和 二次检测以确定一个小分子SR-18292，它可以增加pGC-1的α乙酰化，抑制其 糖异生活性。SR-18292抑制胰高血糖素和前列腺素C-1α依赖的糖异生基因表达 通过增加pGC-1α与GCN5乙酰转移酶的结合，取代转录 糖异生启动子中的HNF4因子α和减少表观遗传组蛋白激活标记。在糖尿病中 SR-18292可降低小鼠的肝脏葡萄糖输出量、高血糖，并增加肝脏的胰岛素敏感性。 总而言之，这些研究支持将这一途径作为T2D潜在的治疗干预措施。因此， 此应用程序的主要目标是表征SR-18292并优化可能具有 T2D有可能成为一种新的抗糖尿病药物治疗方法。我们将执行一个完整的搜救(结构和 活性关系)、DMPK(药物代谢和药代动力学)、毒性和一系列体外和体内试验 体内代谢研究以验证该途径并确定具有强大抗糖尿病作用的SR-18292类似物 活动。实验设计主要集中在两个目标上：1)基于SR-18292的合成孔径雷达和去甲壳蛋白的研究 分子支架的体外和体内实验及靶标鉴定(特异靶1)和2)毒理学 以及使用SR-18292类似物的体内代谢研究(特定目标2)。这项提议的结果将是 为SR-18292类似物作为治疗性药物的早期临床前验证做出重大贡献 T2D和胰岛素抵抗的管理线索。