Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
基本信息
- 批准号:10561676
- 负责人:
- 金额:$ 32.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-09-30 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdhesionsAftercareAntineoplastic AgentsApoptosisBRAF geneBindingBiologicalBiological AssayCell LineCell SurvivalCell modelCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexCrystallizationCrystallographyDataDependenceDevelopmentDrug KineticsDrug TargetingEngineeringEnzymesEvaluationExtracellular MatrixFocal Adhesion Kinase 1Focal AdhesionsFundingGenesGeneticImmune Cell SuppressionIn VitroInvadedLeadMalignant NeoplasmsMass Spectrum AnalysisMeasuresMediatingMelanoma CellMolecularMonitorMutationNeoplasm MetastasisNormal tissue morphologyOncologyOutcomePathway interactionsPatientsPeptidesPermeabilityPharmaceutical PreparationsPhase I Clinical TrialsPhase II Clinical TrialsPhosphotransferasesProgress ReportsProliferatingPropertyProtein Tyrosine KinaseProteinsProteomicsProto-Oncogene Proteins c-aktRas/RafRegulationResearchResistanceRoentgen RaysRoleScaffolding ProteinSeriesSignal PathwaySignal TransductionSkin CancerSolid NeoplasmTalinTechniquesTertiary Protein StructureTestingTherapeuticTumor Biologyangiogenesisanti-cancercancer cellcancer subtypescell motilityimprovedin vivoinhibitorinhibitor therapykinase inhibitormelanomamigrationmouse modelmutantmyristoylationnanomolarnoveloverexpressionpatient derived xenograft modelpaxillinprotein complexresponsescaffoldstapled peptidetargeted treatmenttumortumor progressiontumor xenograft
项目摘要
PROJECT ABSTRACT
Focal Adhesion Kinase (FAK) is a multifunctional non-receptor tyrosine kinase and scaffolding protein that is
overexpressed in numerous solid tumors including melanoma, while minimally expressed in normal tissue. FAK
has been widely investigated as a cancer drug target due its contribution in multiple aspects of tumor progression,
including adhesion, invasion, proliferation, survival, metastasis, angiogenesis, and immune cell suppression.
However, development of FAK inhibitors has largely focused on inhibition of the kinase enzyme of FAK opposed
to inhibition of key scaffolding interactions. Particularly, limited efforts have been made at the discovery and
biological evaluation of inhibitors of the focal adhesion targeting (FAT) scaffolding domain of FAK, the domain
required for FAK localization to focal adhesions. During this period of support, we have identified the first
discovered stapled peptide-based FAK inhibitor (UA-1907) that binds to and co-crystallizes with the FAT domain,
and competitively inhibits FAK-paxillin binding. We have identified a myristoylated derivative (UA-2012) with
improved cellular potency, favorable drug-like properties, and in vivo efficacy; and developed a bivalent peptide
(UA-2023) with low nanomolar binding to FAT. However, the mechanistic differences between these novel FAT
domain peptides and traditional FAK-kinase inhibitors on perturbation of focal adhesion complexes and the FAK
interactome have yet to be elucidated. Furthermore, we have preliminary data showing that FAT inhibition
provides selective anti-cancer effects in NRAS mutant melanoma cells. Melanoma is the deadliest form of skin
cancer and there are no current effective targeted therapies against NRAS mutant melanoma, which represents
~30% of all patients. We hypothesize that FAK FAT domain inhibitors have distinct biological effects on
the focal adhesion complex in cancer cells compared to FAK kinase inhibitors; and cancer cells with
alterations in NRAS signaling pathways have a molecular dependence on FAK FAT scaffolding for
survival, thus promoting selective anti-cancer efficacy. In specific aim 1, we will identify the unique
differences between FAK FAT scaffold inhibitors and FAK kinase inhibitors on modulation of the focal adhesion
complex and the FAK interactome. In specific aim 2, we will define the molecular mechanisms of
sensitivity/resistance to FAK FAT inhibition in melanoma cells with activating mutations in NRAS and BRAF
pathways. In specific aim 3, we will evaluate in vivo efficacy of novel FAK FAT domain inhibitors in mouse models
of NRAS and BRAF driven cancer. Overall, in this project we will utilize FAT stapled peptides to validate that
FAT domain targeting provides additional biological efficacy on the focal adhesion complex compared to FAK-
kinase inhibitors and that NRAS mutant melanoma has a unique sensitivity to FAK FAT inhibition.
.
项目摘要
粘着斑激酶(FAK)是一种多功能的非受体酪氨酸激酶和支架蛋白,
在许多实体瘤包括黑色素瘤中过表达,而在正常组织中表达最低。FAK
由于其在肿瘤进展的多个方面的贡献,
包括粘附、侵袭、增殖、存活、转移、血管生成和免疫细胞抑制。
然而,FAK抑制剂的开发主要集中在抑制FAK的激酶,
抑制关键的脚手架相互作用。特别是,在发现和发现的过程中所做的努力有限,
对FAK的粘着斑靶向(FAT)支架结构域(结构域)抑制剂的生物学评价
所需的FAK本地化局灶性粘连。在这段支持期间,我们确定了第一个
发现了基于钉合肽的FAK抑制剂(UA-1907),其与FAT结构域结合并共结晶,
并竞争性抑制FAK-桩蛋白结合。我们已经鉴定了肉豆蔻酰化衍生物(UA-2012),
改善的细胞效能、有利的药物样性质和体内功效;并开发了二价肽
(UA-2023)具有低纳摩尔的与FAT的结合。然而,这些新型FAT之间的机械差异
结构域肽和传统的FAK激酶抑制剂对粘着斑复合物和FAK扰动的影响
相互作用组尚未阐明。此外,我们有初步的数据表明,脂肪抑制,
在NRAS突变黑素瘤细胞中提供选择性抗癌作用。黑色素瘤是最致命的皮肤病
目前还没有针对NRAS突变型黑色素瘤的有效靶向疗法,这代表了
约30%的患者。我们假设FAK FAT结构域抑制剂对细胞凋亡具有不同的生物学效应。
与FAK激酶抑制剂相比,癌细胞中的粘着斑复合物;
NRAS信号通路的改变对FAK FAT支架具有分子依赖性,
存活,从而促进选择性抗癌功效。在具体目标1中,我们将确定
FAK FAT支架抑制剂和FAK激酶抑制剂对粘着斑调节的差异
复合物和FAK相互作用组。在具体目标2中,我们将定义
NRAS和BRAF激活突变的黑色素瘤细胞对FAK FAT抑制的敏感性/抗性
途径。在具体目标3中,我们将在小鼠模型中评估新型FAK FAT结构域抑制剂的体内功效
NRAS和BRAF驱动的癌症。总的来说,在这个项目中,我们将利用FAT钉合肽来验证,
与FAK相比,FAT结构域靶向对粘着斑复合物提供了额外的生物学功效。
激酶抑制剂,且NRAS突变型黑素瘤对FAKFAT抑制具有独特敏感性。
.
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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Timothy A Marlowe其他文献
Timothy A Marlowe的其他文献
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{{ truncateString('Timothy A Marlowe', 18)}}的其他基金
Discovery of PPI inhibitors for the FAK FAT domain
发现 FAK FAT 结构域的 PPI 抑制剂
- 批准号:
10576504 - 财政年份:2022
- 资助金额:
$ 32.52万 - 项目类别:
Development of Non-Catalytic Peptide Inhibitors of Focal Adhesion Kinase (FAK) for Use in Melanoma
开发用于治疗黑色素瘤的粘着斑激酶 (FAK) 非催化肽抑制剂
- 批准号:
10326066 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
Development of Non-Catalytic Peptide Inhibitors of Focal Adhesion Kinase (FAK) for Use in Melanoma
开发用于治疗黑色素瘤的粘着斑激酶 (FAK) 非催化肽抑制剂
- 批准号:
10670300 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
Development of Non-Catalytic Peptide Inhibitors of Focal Adhesion Kinase (FAK) for Use in Melanoma
开发用于治疗黑色素瘤的粘着斑激酶 (FAK) 非催化肽抑制剂
- 批准号:
10468903 - 财政年份:2019
- 资助金额:
$ 32.52万 - 项目类别:
Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
- 批准号:
10366214 - 财政年份:1996
- 资助金额:
$ 32.52万 - 项目类别:
Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
- 批准号:
9761994 - 财政年份:1996
- 资助金额:
$ 32.52万 - 项目类别:
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