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
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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