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.
项目概要/摘要
糖尿病在美国和全球已达到流行病的程度,并且糖尿病伤口受损
愈合是一个重要且日益严重的临床问题。我们研究的长期目标是开发小型
分子疗法有效促进糖尿病伤口愈合。糖尿病伤口缺乏
基质衍生因子 1α (SDF-1α),一种强效趋化因子,参与祖细胞募集、血管生成、
和肉芽组织的形成,通过与 CXCR4 受体结合并建立
趋化梯度。我们前期的研究数据证实,针对SDF-1α/CXCR4信号通路
具有改善糖尿病伤口愈合的巨大潜力。因此,筛选能够
激活CXCR4受体及其下游通路将为糖尿病伤口愈合提供新的疗法,
并具有巨大的临床应用和商业化潜力。在我们之前的RO1(R01DK105010,
鉴定CXCR4受体激动剂以改善糖尿病伤口愈合),我们筛选了整个NIH SMR
使用我们强大的测试漏斗包含 > 370k 分子的库,并鉴定了 303 种先导化合物。这些导致
通过反筛选、二次趋化/迁移测定及其它们的作用进一步验证了化合物
能够纠正 microRNA-146a、15b 和 29a 的异常表达,从而识别出 2 个先导
脚手架。在一项激动人心的初步研究中,我们测试了我们的先导支架 CAG1 改善糖尿病的能力
注射到小鼠糖尿病伤口后伤口愈合。我们发现单次 CAG1 注射会产生
显着提高糖尿病伤口闭合率,但最佳配方和机制
的修正仍有待确定。这项工作的目的是确定我们的小说小人物的能力
分子CXCR4激动剂纠正体内糖尿病伤口愈合障碍,优化配方
使用药物化学方法进行体外和体内药代动力学研究,确定其机制
行动,然后将这些观察结果扩展到临床相关的猪模型。具体如下
提出的目标: 具体目标 1:对 5-芳基恶唑和三唑进行先导化合物优化
采用构效关系药物化学方法测定噻二嗪系列
化合物体外初级和功能测定中的 EC50 值,CXCR4 结合测定中的 KD 值
并确定 miR15b 和 miR29a 对人糖尿病成纤维细胞表达的影响。具体目标2:
进行体外稳定性、皮肤渗透性和代谢研究并确定其机制
在小鼠伤口愈合模型中对化合物进行糖尿病伤口愈合校正
第 4 层。具体目标 3:识别第 5 层中的 CAG1 或 CAG2 先导化合物并验证 CXCR4
激动剂可纠正糖尿病伤口愈合障碍,并且对临床前猪无毒
模型。
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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