Advancing small molecule CXCR4 agonists for diabetic wound healing
推进小分子 CXCR4 激动剂促进糖尿病伤口愈合
基本信息
- 批准号:10629155
- 负责人:
- 金额:$ 46.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgonistAmputationAnimalsArchitectureAreaBindingBiological AssayCXCR4 ReceptorsCXCR4 Signaling PathwayCXCR4 geneChemotaxisClinicalCollagenDataDiabetes MellitusDrug KineticsEpidemicEpitheliumFibroblastsFormulationGene ExpressionGoalsGranulation TissueHealth ExpendituresHistologyHumanImmunohistochemistryImpaired wound healingImpairmentIn VitroIndividualInflammationInjectionsLeadLibrariesLower ExtremityMeasurementMeasuresMediatingMessenger RNAMicroRNAsMigration AssayMusOxazolesPathway interactionsPatient-Focused OutcomesPermeabilityPharmaceutical ChemistryProductionProteinsResearchSeriesSkinSkin wound healingSocietiesStructure-Activity RelationshipTestingToxic effectUnited StatesUnited States National Institutes of HealthWestern BlottingWorkWound modelsanalogangiogenesischemokineclinical applicationclinically relevantcommercializationcounterscreendiabeticdiabetic patientdiabetic ulcerdiabetic wound healingeffective therapyhealingimprovedin vivolead optimizationmetabolic abnormality assessmentmigrationmouse modelnon-healing woundsnovelnovel therapeuticsporcine modelpre-clinicalrecruitscaffoldscreeningsmall moleculesmall molecule therapeuticsstem cellswoundwound closurewound healing
项目摘要
Project Summary/Abstract
Diabetes has reached epidemic proportions in the United States and globally, and impaired diabetic wound
healing is a significant and growing clinical problem. The long-term goal of our research is to develop small
molecule therapeutics to effectively promote healing of diabetic wounds. Diabetic wounds are deficient in
stromal derived factor-1α (SDF-1α), a potent chemokine involved in progenitor cell recruitment, angiogenesis,
and granulation tissue formation, mediated through binding to the CXCR4 receptor and the establishment of a
chemotactic gradient. Our previous research data confirmed that targeting SDF-1α/CXCR4 signaling pathway
has great potential to improve diabetic wound healing. Therefore, screening small molecule agonists that can
activate CXCR4 receptor and its downstream pathway will provide a novel therapy for diabetic wound healing,
and has great potential for clinical application and commercialization. In our previous RO1 (R01DK105010,
Identifying CXCR4 receptor agonists to improve diabetic wound healing), we screened the entire NIH SMR
library of >370k molecules using our robust testing funnel and identified 303 lead compounds. These lead
compounds were further validated with by counter-screen, secondary chemotaxis/migration assays, and their
ability to correct abnormal expression of microRNA-146a, 15b, and 29a, resulting in the identification of 2 lead
scaffolds. In an exciting preliminary study we tested the ability of our lead scaffold CAG1 to improve diabetic
wound healing following injection into murine diabetic wounds. We found that a single CAG1 injection resulted
in a significant improvement in the rate of diabetic wound closure, but the optimal formulation and mechanisms
of correction remain to be determined. The objective of this work is to determine the ability of our novel small
molecule CXCR4 agonists to correct the diabetic wound healing impairment in vivo, optimize the formulation
and pharmacokinetics in vitro and in vivo using a medicinal chemistry approach, determine the mechanisms of
action, and then extend these observations to the clinically relevant porcine model. The following Specific
Aims are proposed: Specific aim 1: Conduct lead optimization of the 5-aryl oxazole and triazolo
thiadiazine series using structure- activity- relationship medicinal chemistry approaches, Determine
compound in vitro EC50 values in primary and functional assays, KD values in a CXCR4 binding assay
and determine effect on human diabetic fibroblast expression of miR15b, and miR29a. Specific aim 2:
Perform in vitro stability, skin permeability and metabolism studies and determine the mechanisms of
diabetic wound healing correction in a murine model of wound healing for compounds advancing to
tier 4. Specific aim 3: Identify a CAG1 or CAG2 lead compound in tier 5 and Validate that CXCR4
agonist corrects the diabetic wound healing impairment and is non-toxic in a pre-clinical porcine
model.
项目总结/文摘
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Discovery of Small Molecule Activators of Chemokine Receptor CXCR4 That Improve Diabetic Wound Healing.
发现可改善糖尿病伤口愈合的趋化因子受体 CXCR4 小分子激活剂。
- DOI:10.3390/ijms23042196
- 发表时间:2022-02-16
- 期刊:
- 影响因子:5.6
- 作者:Xu J;Hu J;Idlett-Ali S;Zhang L;Caples K;Peddibhotla S;Reeves M;Zgheib C;Malany S;Liechty KW
- 通讯作者:Liechty KW
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KENNETH W LIECHTY其他文献
KENNETH W LIECHTY的其他文献
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{{ truncateString('KENNETH W LIECHTY', 18)}}的其他基金
Advancing small molecule CXCR4 agonists for diabetic wound healing
推进小分子 CXCR4 激动剂促进糖尿病伤口愈合
- 批准号:
10805959 - 财政年份:2023
- 资助金额:
$ 46.99万 - 项目类别:
Advancing small molecule CXCR4 agonists for diabetic wound healing
推进小分子 CXCR4 激动剂促进糖尿病伤口愈合
- 批准号:
10227231 - 财政年份:2020
- 资助金额:
$ 46.99万 - 项目类别:
Advancing small molecule CXCR4 agonists for diabetic wound healing
推进小分子 CXCR4 激动剂促进糖尿病伤口愈合
- 批准号:
10393038 - 财政年份:2020
- 资助金额:
$ 46.99万 - 项目类别:
Modulation of Inflammation and Oxidative Stress in Diabetic Wound Healing
糖尿病伤口愈合中炎症和氧化应激的调节
- 批准号:
9752906 - 财政年份:2019
- 资助金额:
$ 46.99万 - 项目类别:
Modulation of Inflammation and Oxidative Stress in Diabetic Wound Healing
糖尿病伤口愈合中炎症和氧化应激的调节
- 批准号:
9908072 - 财政年份:2019
- 资助金额:
$ 46.99万 - 项目类别:
Modulation of Inflammation and Oxidative Stress in Diabetic Wound Healing
糖尿病伤口愈合中炎症和氧化应激的调节
- 批准号:
10368132 - 财政年份:2019
- 资助金额:
$ 46.99万 - 项目类别:
Modulation of Inflammation and Oxidative Stress in Diabetic Wound Healing
糖尿病伤口愈合中炎症和氧化应激的调节
- 批准号:
10811436 - 财政年份:2019
- 资助金额:
$ 46.99万 - 项目类别:
Identifying CXCR4 Receptor Agonists to Improve Diabetic Healing
鉴定 CXCR4 受体激动剂以改善糖尿病愈合
- 批准号:
9294130 - 财政年份:2016
- 资助金额:
$ 46.99万 - 项目类别:
Identifying CXCR4 Receptor Agonists to Improve Diabetic Healing
鉴定 CXCR4 受体激动剂以改善糖尿病愈合
- 批准号:
9175599 - 财政年份:2016
- 资助金额:
$ 46.99万 - 项目类别:
Identifying CXCR4 Receptor Agonists to Improve Diabetic Healing
鉴定 CXCR4 受体激动剂以改善糖尿病愈合
- 批准号:
8995740 - 财政年份:2015
- 资助金额:
$ 46.99万 - 项目类别:
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