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:
- 金额:$ 63.66万
- 依托单位:
- 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:
- 关键词:AddressAmes AssayAmino AcidsAnilineAnimalsAnterior Descending Coronary ArteryAntibodiesArterial InjuryAtherosclerosisAttenuatedBackBenchmarkingBindingBioavailableBiological AssayBiological AvailabilityBiophysicsCanis familiarisCardiac MyocytesCellsChemistryComplications of Diabetes MellitusCoupledCultured CellsCytoplasmic TailDataDelayed HypersensitivityDevelopmentDiabetes MellitusDiabetic NephropathyDiabetic mouseDiseaseDrug DesignDrug InteractionsDrug KineticsEndothelial CellsEpithelial CellsEvaluationExtracellular DomainFamily suidaeFemaleFoundationsGenesGeneticGoalsGrantImmunoglobulin DomainImpaired wound healingIn VitroIndolesInflammationInsulin-Dependent Diabetes MellitusInterdisciplinary StudyKidneyKidney DiseasesLaboratoriesLeadLeftLigand BindingLigandsLigationMediatingMedicalMetabolic ActivationModelingModificationMorbidity - disease rateMusMutationMyocardial IschemiaNMR SpectroscopyNational Institute of Diabetes and Digestive and Kidney DiseasesNon-Insulin-Dependent Diabetes MellitusOralPathologyPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPositioning AttributePropertyProteinsRattusReperfusion InjuryReperfusion TherapyResearchRiskRodentSafetySelection CriteriaSeriesSignal TransductionSiteSmooth Muscle MyocytesSpecificityStructureStructure-Activity RelationshipTestingTherapeuticTissuesToxicity TestsTreatment EfficacyValidationWorkanalogbasecandidate selectioncell transformationclinical developmentdata modelingdesigndrug discoveryexperimental studyextracellularhigh throughput screeningin vivoin vivo Modellead candidatelead optimizationlead seriesmacrophagemacrovascular diseasemalemortalitymultidisciplinarymyocardial infarct sizingnovelnovel therapeutic interventionprogramsreceptor for advanced glycation endproductsresearch clinical testingresponsesafety studyscaffoldscreeningsmall moleculesmall molecule librariestherapeutic 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.
抽象的
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 型糖尿病患者发病和死亡的主要原因。 RAGE 细胞外结构域
是异质的,RAGE 配体可能结合在这些结构域上空间上不同的位点,从而表明
使用针对细胞外结构域的小分子或抗体可能无效。我们有
发现 RAGE (ctRAGE) 的细胞质尾部与细胞内福明分子的相互作用,
DIAPH1 对于 RAGE 介导的信号转导至关重要。我们之前进行了高通量筛选
超过 59,000 种化合物,旨在阻断 ctRAGE 与 DIAPH1 的相互作用。我们确定了两个线索
满足类药特性关键标准的系列(LS); RAGE229 是该系列之一的 LSII 中的一员
由于功效、良好的药代动力学特征和前景,可能成为临床开发的先导
早期脱靶和毒性测试。体内功效也得到了证明,如施用 RAGE229
在小鼠迟发型超敏反应实验中减轻炎症,减少心肌梗塞面积
糖尿病小鼠的左冠状动脉前降支结扎和再灌注后,
糖尿病相关肾脏病理学的多个参数和糖尿病小鼠伤口愈合受损,所有
与媒介物相比,在雄性和雌性小鼠中。然而,在后期测试中,RAGE229 在
迷你 AMES 测试。为了解决这个问题,我们已经准备了 RAGE229 的新类似物;这些类似物
保留效力,但在 Mini-AMES 测试中呈阴性。此外,我们在以下方面也取得了重大进展:
在 LS I 中开发备用候选药物。重要的是,LSI 中的一种主要基准化合物测试结果呈阴性
在 Mini-AMES 测试中也是如此。我们成熟的多学科团队现已做好准备继续前进
在此关键时刻积极寻找 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) 鉴定 LSII 的有效、选择性和安全的候选类似物; 2) 开发LSI备份
具有不同支架的候选人可以降低我们 RAGE 计划的风险。如果成功的话,我们的工作将设定
新型糖尿病疾病缓解剂的开发和临床测试阶段
并发症。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Ravichandran Ramasamy其他文献
Ravichandran Ramasamy的其他文献
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{{ truncateString('Ravichandran Ramasamy', 18)}}的其他基金
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
- 批准号:
10368080 - 财政年份:2020
- 资助金额:
$ 63.66万 - 项目类别:
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
- 批准号:
10596466 - 财政年份:2020
- 资助金额:
$ 63.66万 - 项目类别:
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
- 批准号:
10055037 - 财政年份:2020
- 资助金额:
$ 63.66万 - 项目类别:
Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗死
- 批准号:
10191021 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10191020 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10642706 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
Core 2: Mouse, Cell and Protein Support, Data Management and Biostatistics Core
核心 2:小鼠、细胞和蛋白质支持、数据管理和生物统计学核心
- 批准号:
10407556 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗塞
- 批准号:
10642708 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
Project 1:Diabetes, RAGE/DIAPH1 and Myocardial Infarction
项目1:糖尿病、RAGE/DIAPH1与心肌梗死
- 批准号:
10407557 - 财政年份:2019
- 资助金额:
$ 63.66万 - 项目类别:
RAGE/mDia1, Macrophage Trafficking and Inflammation in High Fat Feeding
RAGE/mDia1、高脂肪喂养中的巨噬细胞运输和炎症
- 批准号:
9906204 - 财政年份:2016
- 资助金额:
$ 63.66万 - 项目类别:














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