Discovery of PPI inhibitors for the FAK FAT domain
发现 FAK FAT 结构域的 PPI 抑制剂
基本信息
- 批准号:10576504
- 负责人:
- 金额:$ 21.53万
- 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:2022-12-09 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffinityAntineoplastic AgentsApoptosisApoptoticBindingBinding SitesBiochemicalBiologicalBiological AssayBiological AvailabilityBiophysicsBreastC-terminalCD47-SIRPαCell AdhesionCellsCellular AssayChemicalsClinicalClinical TrialsColorectalColorectal CancerComplexCytostaticsDCC geneDataDevelopmentDimethyl SulfoxideDominant-Negative MutationDrug KineticsDrug ScreeningDrug TargetingEngineeringEpitheliumFluorescence Resonance Energy TransferFocal Adhesion Kinase 1Focal AdhesionsFutureGlioblastomaHydrocarbonsInduction of ApoptosisInvadedKnockout MiceLabelLaboratoriesLeadLibrariesLigandsLymphangiogenesisMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMalignant neoplasm of pancreasMapsMeasuresMediatingMelanoma CellMesenchymalMorphologic artifactsMutationN-terminalNeoplasm MetastasisNormal CellOncogenicOralOvarianPI3K/AKTPancreasPathway interactionsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhase I/II Clinical TrialPhosphotransferasesProliferatingProtein IsoformsProtein Tyrosine KinaseProteinsRegional CancerReportingResearchResearch Project GrantsRoleScaffolding ProteinSeriesSignal PathwaySignal TransductionSolid NeoplasmSystemTechnologyTertiary Protein StructureTestingTherapeuticTransfectionalpha helixanalogangiogenesisanti-cancerbeta cateninbiophysical techniquescancer cellcancer therapycell motilitycomparative efficacycounterscreencytotoxicitydesignexperimental studygenetic manipulationimprovedin vivoinhibitorinnovationkinase inhibitorknock-downleupaxinmelanomametermigrationmutantmyristoylationnovelnovel therapeuticsoverexpressionpaxillinpeptide drugpeptidomimeticspharmacologicprotein protein interactionrecruitresponsescaffoldscreeningsmall moleculestapled peptidetargeted cancer therapytargeted treatmenttumor growthtumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
Focal adhesion kinase (FAK), or protein tyrosine kinase 2 (PTK2), is a 125 kDa non-receptor tyrosine kinase
and scaffolding protein that is overexpressed or amplified in many cancers, including ovarian, breast, colorectal,
melanoma, glioblastoma, and pancreatic cancers. FAK is involved in multiple biological pathways that can
contribute to cancer progression, including cell migration, invasion, lymphangiogenesis, anti-apoptosis,
metastasis, epithelial-mesenchymal transition (EMT), and signaling pathways mediated by PI3K/AKT and β-
catenin. FAK has been validated as a target in cancer therapy by genetic manipulation, and FAK knockdown
results in robust activation of apoptosis in cancer cells, with minimal effects in normal cells. Many ATP-
competitive FAK kinase domain inhibitors have been reported; however, these are only cytostatic and/or
moderately selective for FAK, and have shown limited efficacy in clinical trials. Kinase-independent roles of FAK
are not blocked by kinase inhibition; in particular, the scaffolding function of the C-terminal focal adhesion
targeting (FAT) domain. The FAK FAT domain is the major modulator of FAK-dependent anti-apoptosis and is
the domain regulated by the endogenous dominant-negative FAK isoform termed FAK-related non-kinase
(FRNK). Specifically, the FAT-paxillin protein-protein interaction (PPI) localizes FAK to the focal adhesion, and
mutation of residues at the FAT domain interface perturbs focal adhesion turnover, cell adhesion, migration, and
invasion. Thus, a major unmet need is the discovery of small molecule chemical probes that block FAK FAT
domain scaffolding. In order to target the FAK FAT domain, we have previously explored fragment screening by
SPR/NMR and hydrocarbon-stapled peptides. These approaches led to FAT fragment-based hits with
micromolar affinity and the lead stapled peptide probe, UA-1907 (KD = 1 µM) that induces apoptosis in melanoma
cells. For this project, we will develop novel drug screening assays leveraging chemical probe UA-1907 to identify
small molecule FAT ligands that disrupt the anti-apoptotic scaffolding functions of FAK. Specifically, we will: 1)
design a TR-FRET biochemical assay to screen a 35,000 compound PPI-biased library for hits that inhibit UA-
1907 binding to FAT; 2) confirm biochemical hits as FAT ligands using SPR and HSQC-NMR approaches; and
3) develop a NanoBiT cellular assay measuring FAK-paxillin binding to validate hits. In all, we expect this project
to identify the first described small molecule-based inhibitors of the FAT-paxillin interaction that will serve as the
basis for future medicinal chemistry optimization studies.
项目总结/文摘
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
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:
$ 21.53万 - 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:
$ 21.53万 - 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:
$ 21.53万 - 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:
$ 21.53万 - 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:
10561676 - 财政年份:1996
- 资助金额:
$ 21.53万 - 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:
$ 21.53万 - 项目类别:
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