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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：
10055037
负责人：
Ravichandran Ramasamy
金额：
$ 67.2万
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/10055037
关键词：
Address Ames Assay Amino Acids Aniline Animals Anterior Descending Coronary Artery Antibodies Arterial Injury Atherosclerosis Attenuated Back Benchmarking Binding Bioavailable 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 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 therapeutics programs receptor for advanced glycation endproducts research clinical testing response safety study scaffold screening small molecule small molecule libraries therapeutic evaluation

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.

摘要糖尿病的并发症，特别是伤口愈合受损和糖尿病相关肾病， 1型和2型糖尿病患者发病率和死亡率的主要原因。细胞外结构域是异质性的，并且配体可以在这些结构域上的空间上不同的位点结合，从而表明使用靶向细胞外结构域的小分子或抗体可能无效。我们有发现胞质尾区（ctfl）与胞内tfl分子的相互作用， DIAPH 1是RAGE介导的信号转导所必需的。我们之前进行了高通量筛选 > 59，000种化合物，目的是阻断CTALINE与DIAPH 1的相互作用。我们找到了两个线索系列（LS），满足药物样性质的关键标准;从一个系列，LSII，RAGE 229出现作为一个由于有效性、有利的药代动力学特征和有前景的早期脱靶和毒性测试。体内功效也得到证实，因为施用RAGE 229 在小鼠迟发型超敏反应实验中减弱炎症，减少心肌梗死面积结扎和再灌注糖尿病小鼠冠状动脉左前降支后，糖尿病小鼠中糖尿病相关肾脏病理学和伤口愈合受损的多个参数，所有在雄性和雌性小鼠中，与溶媒相比。然而，在后期测试中，RAGE 229在 Mini-AMES测试。为了解决这个问题，我们已经制备了RAGE 229的新类似物;这些类似物保留效力，但在Mini-AMES试验中呈阴性。此外，我们还在以下方面取得了重大进展：在LS I中开发后备候选人。重要的是，LSI中的一种铅基准化合物检测呈阴性在Mini-AMES测试中也是如此。我们建立的多学科团队现在已经准备好向前迈进在这个关键时刻，我们积极地确定LSII的主要候选分子和最终的备用LSI。糖尿病并发症的临床发展。我们的药物发现目标，得到了广泛的初步支持，数据是：1）识别LSII的有效，选择性和安全的候选类似物; 2）开发LSI备份候选人与不同的脚手架，以减轻风险，我们的可持续发展计划。如果成功的话，我们的工作将为一种新型糖尿病疾病缓解剂的开发和临床试验阶段并发症