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: 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
• 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

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（T2 D），特别是与肥胖相关的2型糖尿病，在美国和世界范围内是流行病， 这是导致肾脏疾病、非创伤性截肢和失明的主要原因。尽管有 目前用于治疗T2 D的抗糖尿病药物，例如胰岛素促分泌剂和二甲双胍， 迫切需要额外的靶向治疗，以改善对这种疾病的管理， 这些现有药物对患者的疗效中等。随着T2 D的进展， 不受控制的肝葡萄糖产生强烈地促进慢性高血糖症，这是 各种糖尿病病理转录辅激活因子PGC-1α的乙酰化选择性抑制 肝葡萄糖产生并改善T2 D。我们使用了一系列化学高通量和 二次试验，以确定一种小分子SR-18292，它增加PGC-1α乙酰化，抑制其 致热活性。SR-18292抑制胰高血糖素和PGC-1α依赖性促血管生成基因表达 通过增加PGC-1α和GCN 5乙酰转移酶之间的结合，取代转录， 因子HNF 4 α从表观遗传启动子和减少表观遗传组蛋白激活标记。糖尿病 在小鼠中，SR-18292降低肝葡萄糖输出、高血糖症并增加肝胰岛素敏感性。 总之，这些研究支持靶向这一途径，用于T2 D的潜在治疗干预。因此，在本发明中， 本申请的主要目标是表征SR-18292并优化可能具有以下特性的类似物： 有可能成为T2 D的新型抗糖尿病药物治疗。我们将执行一个完整的SAR（结构和 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研究结果， 体内代谢研究，以验证该途径并鉴定具有强效抗糖尿病作用的SR-18292类似物 活动实验设计主要有两个目的：1）基于SR-18292的SAR和DMPK研究 使用体外和体内测定和靶点鉴定的分子支架（特定目的1）和，2）毒理学 和使用SR-18292类似物的体内代谢研究（特定目的2）。该提案的结果将 为SR-18292类似物作为治疗药物的早期临床前验证做出了重大贡献 治疗2型糖尿病和胰岛素抵抗。

项目成果

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

• DOI: 10.1021/acs.jmedchem.0c01450
• 发表时间: 2021-01-28
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lin H;Sharabi K;Lin L;Ruiz C;Zhu D;Cameron MD;Novick SJ;Griffin PR;Puigserver P;Kamenecka TM
• 通讯作者: Kamenecka TM