Non-catalytic FAK inhibitors as novel therapeutics for lung fibrosis
非催化 FAK 抑制剂作为肺纤维化的新型疗法
基本信息
- 批准号:10385275
- 负责人:
- 金额:$ 29.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-10 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdsorptionAffectAffinityApoptosisAutomobile DrivingBindingBiochemicalBiological AssayBiophysicsBleomycinC57BL/6 MouseCellsChemicalsClinicalCollagenComplexConnective Tissue DiseasesCrystallizationDataDepositionDevelopmentDoseDrug KineticsElderlyEnzymesExcretory functionExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFibronectinsFibrosisFocal Adhesion Kinase 1Focal AdhesionsFormulationFutureGene Expression ProfilingGenerationsGoalsHealthHumanIn VitroInjuryLeadLeftLiposomesLungLung TransplantationLung diseasesMalignant NeoplasmsMeasuresMetabolismMethodsModelingMusMyofibroblastPatientsPeptidesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhasePhenotypePhosphotransferasesPirfenidonePreclinical TestingProductionPrognosisPropertyProteinsPulmonary FibrosisQuality of lifeResistanceRheumatoid ArthritisRoentgen RaysRoleScaffolding ProteinSclerodermaSeriesSliceSmall Business Technology Transfer ResearchSolubilityStructureStructure of parenchyma of lungTestingTherapeuticTissue ModelToxic effectanalogantifibrotic treatmentbasecell motilitydrug developmenteffective therapyefficacy evaluationfibrotic lungidiopathic pulmonary fibrosisimprovedin vitro Assayin vitro testingin vivoin vivo evaluationinhibitorkinase inhibitorlead optimizationlipophilicitylung developmentmelanomamenmolecular modelingmouse modelnintedanibnovelnovel therapeuticspaxillinpeptide analogpreclinical developmentpulmonary function declinescaffoldstapled peptideyoung woman
项目摘要
PROJECT ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal fibrotic lung disorder which
disproportionately affects men and the elderly. Although two drugs (pirfenidone and nintedanib) have recently
gained FDA-approval for IPF and progressive fibrosing lung disorders related to connective tissue diseases
(rheumatoid arthritis and scleroderma, more common in younger women), these drugs are by no means curative.
In fact, these therapies show only a modest reduction in the rate of lung function decline and do not improve
quality of life. Unfortunately, several potential therapies in the fibrosis pipeline have failed to meet their endpoints
in recent trials. Hence, we are left with suboptimal treatments and lung transplantation as the only current
treatment for IPF patients. Importantly, no available therapies ‘reverse’ fibrosis. Focal Adhesion Kinase (FAK) is
a non-receptor tyrosine kinase and scaffolding protein that regulates the pro-fibrotic phenotype of lung
fibroblasts, including secretion of extracellular matrix proteins (fibronectin and collagen), myofibroblast
differentiation, cell migration, and resistance to apoptosis. In recent analyses of gene expression in lung tissue
from IPF patients, FAK is highly upregulated in both early IPF and advanced IPF compared to health controls.
Moreover, the scaffolding function of the Focal Adhesion Targeting (FAT) domain of FAK has been
demonstrated to be critical for the development of lung fibrosis in vitro and in vivo. However, the FAK
inhibitors developed to date only target its kinase enzyme and ignore FAK’s role as a scaffolding protein.
Because current FAK-kinase inhibitors do not inhibit key FAT domain interactions in lung fibroblasts and show
high off-target toxicity, the development of novel FAK inhibitors that target the non-catalytic scaffolding function
or FAT domain of FAK remains a significant unmet clinical need. FAKnostics, LLC has identified a first-in-class
series of stapled peptide-based FAK inhibitors that directly target the FAT domain of FAK. We have preliminary
data that lead peptide FN-2023 causes potent anti-fibrotic effects in lung fibroblasts (IMR90), including reduction
in protein levels of α-SMA, fibronectin, and collagen. The goal of this Phase I STTR is to demonstrate proof-
of-concept for the use of these novel FAK FAT inhibitors as therapeutics of lung fibrosis. In Aim 1, we
will optimize lead peptide FN-2023 to improve ADMET properties. In Aim 2, we will characterize optimized
peptides for anti-fibrotic effects on lung fibroblasts and precision cut lung slices (PCLS). In Aim 3, we will
evaluate in vivo pharmacokinetics of top optimized peptides and test using an in vivo efficacy model of lung
fibrosis (bleomycin injury model). Ultimately, this project will result in optimized FAK FAT peptides that show
improved ADMET properties and efficacy in a mouse model of lung fibrosis, supporting further preclinical
development in a future Phase II project.
项目摘要
特发性肺纤维化(IPF)是一种持续进展性和致命性纤维性肺疾病,
对男性和老年人的影响不成比例。虽然最近有两种药物(吡非尼酮和九替达尼)
获得FDA批准用于IPF和与结缔组织病相关的进行性纤维化性肺疾病
(类风湿性关节炎和硬皮病,在年轻女性中更常见),这些药物绝不是治愈的。
事实上,这些疗法仅显示肺功能减退率略有下降,而且没有改善。
生活质量。不幸的是,纤维化管道中的几种潜在治疗方法未能达到它们的终点
在最近的审判中。因此,我们只剩下次优治疗和肺移植作为唯一的治疗方法。
IPF患者的治疗。重要的是,目前还没有可用的治疗方法来“逆转”纤维化。粘着斑激酶(FAK)是
一种调节肺纤维化前表型的非受体酪氨酸激酶和支架蛋白
成纤维细胞,包括分泌细胞外基质蛋白(纤维连接蛋白和胶原)、肌成纤维细胞
分化、细胞迁移和抗凋亡。肺组织基因表达的最新研究进展
在IPF患者中,与健康对照组相比,FAK在早期IPF和晚期IPF中都高度上调。
此外,FAK的焦点黏附靶向(FAT)结构域的支架功能已经被
已证实在体外和体内肺纤维化的发生发展中起关键作用。然而,FAK
到目前为止,开发的抑制剂只针对其激酶酶,而忽略了FAK作为支架蛋白的作用。
因为目前的FAK-Kinase抑制剂不能抑制肺成纤维细胞中关键的脂肪结构域相互作用,并显示
高脱靶毒性,针对非催化支架功能的新型FAK抑制剂的开发
FAK的脂肪领域仍然是一个重要的未得到满足的临床需求。FAKnostics,LLC已经确定了一流的
一系列基于装订的多肽的FAK抑制剂,直接针对FAK的脂肪域。我们有初步的
数据表明,先导肽FN-2023对肺成纤维细胞(IMR90)具有强大的抗纤维化作用,包括减少
α-SMA、纤维连接蛋白和胶原蛋白的蛋白水平。这一第一阶段STTR的目标是证明-
-使用这些新的FAK脂肪抑制剂作为肺纤维化治疗的概念。在目标1中,我们
将优化先导肽FN-2023,以改善ADMET的性能。在目标2中,我们将描述优化后的
用于肺成纤维细胞和精密肺切片(PCLS)的抗纤维化作用的多肽。在《目标3》中,我们将
TOP优化肽的体内药代动力学评价及肺脏体内药效模型试验
肝纤维化(博莱霉素损伤模型)。最终,这个项目将产生优化的FAK脂肪肽,显示
改善肺纤维化小鼠模型的ADMET特性和疗效,支持进一步的临床前研究
未来第二阶段项目的发展。
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)
专利数量(0)
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KENNETH S KNOX其他文献
KENNETH S KNOX的其他文献
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{{ truncateString('KENNETH S KNOX', 18)}}的其他基金
Genomic Analysis of Immunity and Lung Inflammation in HIV Infection
HIV 感染中免疫和肺部炎症的基因组分析
- 批准号:
8904713 - 财政年份:2013
- 资助金额:
$ 29.99万 - 项目类别:
Genomic Analysis of Immunity and Lung Inflammation in HIV Infection
HIV 感染中免疫和肺部炎症的基因组分析
- 批准号:
9323500 - 财政年份:2013
- 资助金额:
$ 29.99万 - 项目类别:
Genomic Analysis of Immunity and Lung Inflammation in HIV Infection
HIV 感染中免疫和肺部炎症的基因组分析
- 批准号:
8639210 - 财政年份:2013
- 资助金额:
$ 29.99万 - 项目类别:
PULMONARY CD4+ T-CELL RE-POPULATION IN IMMUNE RECONSTITUTION SYNDROME
免疫重建综合征中肺 CD4 T 细胞的重新增殖
- 批准号:
7717564 - 财政年份:2007
- 资助金额:
$ 29.99万 - 项目类别:
PULMONARY CD4+ T-CELL RE-POPULATION IN IMMUNE RECONSTITUTION SYNDROME
免疫重建综合征中肺 CD4 T 细胞的重新增殖
- 批准号:
7606467 - 财政年份:2006
- 资助金额:
$ 29.99万 - 项目类别:
Pulmonary CD4+ T-Cell Repopulation in Immune Reconstitu*
免疫重建中的肺 CD4 T 细胞增殖*
- 批准号:
7126010 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Pulmonary CD4+ T-Cell Repopulation in Immune Reconstituion Syndrome
免疫重建综合征中的肺 CD4 T 细胞增殖
- 批准号:
7688565 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Pulmonary CD4+ T-Cell Repopulation in Immune Reconstitu*
免疫重建中的肺 CD4 T 细胞增殖*
- 批准号:
7036411 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Pulmonary CD4+ T-Cell Repopulation in Immune Reconstituion Syndrome
免疫重建综合征中的肺 CD4 T 细胞增殖
- 批准号:
7448545 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
Pulmonary CD4+ T-Cell Repopulation in Immune Reconstituion Syndrome
免疫重建综合征中的肺 CD4 T 细胞增殖
- 批准号:
7264485 - 财政年份:2005
- 资助金额:
$ 29.99万 - 项目类别:
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