Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications

靶向 RAGE/DIAPH1：糖尿病并发症的新治疗策略

基本信息

批准号：
10368080
负责人：
Ravichandran Ramasamy
金额：
$ 61.99万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368080
关键词：
Address Ames Assay Amino Acids Aniline Animals Anterior Descending Coronary Artery Antibodies Arterial Injury Atherosclerosis Attenuated Back Benchmarking Binding Biological Assay Biological Availability Biophysics Canis familiaris Cardiac Myocytes Cells Chemistry Complications of Diabetes Mellitus Coupled Cultured Cells Cytoplasmic Tail Data Delayed Hypersensitivity Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Drug Design Drug Interactions Drug Kinetics Endothelial Cells Epithelial Cells Evaluation Extracellular Domain Family suidae Female Foundations Genes Genetic Goals Grant Immunoglobulin Domain Impaired wound healing In Vitro Indoles Inflammation Insulin-Dependent Diabetes Mellitus Interdisciplinary Study Kidney Kidney Diseases Laboratories Lead Left Ligand Binding Ligands Ligation Mediating Medical Metabolic Activation Modeling Modification Morbidity - disease rate Mus Mutation Myocardial Ischemia NMR Spectroscopy National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Oral Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Property Proteins Rattus Reperfusion Injury Reperfusion Therapy Research Risk Rodent Safety Selection Criteria Series Signal Transduction Site Smooth Muscle Myocytes Specificity Structure Structure-Activity Relationship Testing Therapeutic Tissues Toxicity Tests Treatment Efficacy Validation Work analog antagonist base candidate selection cell transformation clinical development data modeling design drug discovery experimental study extracellular high throughput screening in vivo in vivo Model lead candidate lead optimization lead series macrophage macrovascular disease male mortality multidisciplinary myocardial infarct sizing novel novel therapeutic intervention programs rational design receptor for advanced glycation endproducts research clinical testing response safety study scaffold screening small molecule small molecule libraries therapeutic evaluation

Address Ames Assay Amino Acids Aniline Animals Anterior Descending Coronary Artery Antibodies Arterial Injury Atherosclerosis Attenuated Back Benchmarking Binding Biological Assay Biological Availability Biophysics Canis familiaris Cardiac Myocytes Cells Chemistry Complications of Diabetes Mellitus Coupled Cultured Cells Cytoplasmic Tail Data Delayed Hypersensitivity Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Drug Design Drug Interactions Drug Kinetics Endothelial Cells Epithelial Cells Evaluation Extracellular Domain Family suidae Female Foundations Genes Genetic Goals Grant Immunoglobulin Domain Impaired wound healing In Vitro Indoles Inflammation Insulin-Dependent Diabetes Mellitus Interdisciplinary Study Kidney Kidney Diseases Laboratories Lead Left Ligand Binding Ligands Ligation Mediating Medical Metabolic Activation Modeling Modification Morbidity - disease rate Mus Mutation Myocardial Ischemia NMR Spectroscopy National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Oral Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Property Proteins Rattus Reperfusion Injury Reperfusion Therapy Research Risk Rodent Safety Selection Criteria Series Signal Transduction Site Smooth Muscle Myocytes Specificity Structure Structure-Activity Relationship Testing Therapeutic Tissues Toxicity Tests Treatment Efficacy Validation Work analog antagonist base candidate selection cell transformation clinical development data modeling design drug discovery experimental study extracellular high throughput screening in vivo in vivo Model lead candidate lead optimization lead series macrophage macrovascular disease male mortality multidisciplinary myocardial infarct sizing novel novel therapeutic intervention programs rational design receptor for advanced glycation endproducts research clinical testing response safety study scaffold screening small molecule small molecule libraries therapeutic evaluation

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项目摘要

Abstract The complications of diabetes, particularly impaired wound healing and diabetes-associated nephropathy, are major causes of morbidity and mortality in patients with types 1 and 2 diabetes. The RAGE extracellular domains are heterogeneous and RAGE ligands may bind at spatially-distinct sites on these domains, thereby indicating that the use of small molecules or antibodies targeted to the extracellular domains, may be ineffective. We have discovered that the interaction of the cytoplasmic tail of RAGE (ctRAGE) with the intracellular formin molecule, DIAPH1, is essential for RAGE-mediated signal transduction. We previously performed a high-throughput screen of >59,000 compounds with the goal to block the interaction of ctRAGE with DIAPH1. We identified two lead series (LS) that fulfill key criteria for drug-like properties; from one of the series, LSII, RAGE229 emerged as a plausible lead for clinical development because of efficacy, favorable pharmacokinetic profile and promising early-stage off-target and toxicity testing. In vivo efficacy was also demonstrated, as administration of RAGE229 attenuated inflammation in a delayed type hypersensitivity experiment in mice, reduced myocardial infarct size upon ligation and reperfusion of the left anterior descending coronary artery in diabetic mice, and reduced multiple parameters of diabetes-associated kidney pathology and impaired wound healing in diabetic mice, all versus vehicle, in both male and female mice. However, in late-stage testing, RAGE229 tested positive in the Mini-AMES test. To address this liability, we have already prepared new analogs of RAGE229; these analogs retain potency but are negative in the Mini-AMES test. In addition, we have made significant progress in developing back-up candidates in the LS I. Importantly, a lead benchmark compound within LSI tested negative in the Mini-AMES test as well. Our established, multi-disciplinary team is now well-poised to move forward aggressively at this critical juncture to identify lead candidate molecules for LSII and the back-up LSI for ultimate clinical development for diabetic complications. Our drug discovery goals, supported by extensive preliminary data are: 1) to identify potent, selective, and safe candidate analogs of LSII; and 2) to develop LSI backup candidates with a different scaffold to mitigate risk to our RAGE program. If successful, our work will set the stage for the development and clinical testing of a novel class of disease-modifying agents for diabetic complications.

抽象的糖尿病的并发症，尤其是伤口愈合受损和与糖尿病相关的肾病的并发症，是 1型和2型糖尿病患者的发病率和死亡率的主要原因。愤怒的细胞外域是否异质和愤怒的配体可能在这些域上的空间赋予位点结合，从而表明使用针对细胞外结构域的小分子或抗体的使用可能是无效的。我们有发现RAGE（CTRAGE）的细胞质尾巴与细胞内formin分子的相互作用， Diaph1对于愤怒介导的信号转导至关重要。我们之前进行了高通量屏幕 > 59,000种化合物的目标是阻止Ctrage与Diaph1的相互作用。我们确定了两个领导符合类似药物的特性的关键标准的系列；从该系列之一的LSII中，Rage229出现为由于功效，有利的药代动力学特征和有希望的临床开发的合理铅早期脱离目标和毒性测试。还证明了体内功效，作为RAGE229的给药在小鼠中延迟类型的超敏反应实验中的炎症减弱，心肌梗塞尺寸降低在糖尿病小鼠的左前冠状动脉结扎和再灌注后，并减少糖尿病小鼠中与糖尿病相关的肾脏病理学和伤口愈合受损的多个参数在男性和雌性小鼠中与车辆相比。但是，在后期测试中，RAGE229在迷你AMES测试。为了解决这一责任，我们已经准备了Rage229的新类似物；这些类似物保留效力，但在迷你AMES测试中为负。此外，我们在重要的是，在LS I中开发备份候选物在迷你AMES测试中。我们既定的，多学科的团队现在已经付出了良好的前进在这个关键时刻积极地识别LSII和备用LSI的铅候选分子以最终糖尿病并发症的临床发育。我们的药物发现目标，由广泛的初步支持数据是：1）确定LSII的有效，选择性和安全的候选类似物； 2）开发LSI备份具有不同脚手架的候选人可以减轻我们的愤怒计划的风险。如果成功，我们的工作将确定糖尿病的新型疾病改良剂的开发和临床测试的阶段并发症。