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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：
10197120
负责人：
Ravichandran Ramasamy
金额：
$ 63.66万
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/10197120
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 therapeutic intervention 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