Applying Chemical Biology to Target Deubiquitinating Enzymes in Lung Cancer
Applying Chemical Biology to Target Deubiquitinating Enzymes in Lung Cancer
批准号:
9375662
负责人:
ERIC B. HAURA
金额:
$22.45万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-03 至 2019-07-31
关键词:
Active SitesAdenocarcinomaAffectBiologicalBiological AssayBiologyCancer cell lineCell LineCell SurvivalCellsChemicalsChemistryComputer softwareDataDetectionDeubiquitinating EnzymeDiseaseDrug TargetingElementsEnzyme Inhibitor DrugsEnzymesEpidermal Growth Factor ReceptorExcisionFamilyGeneticGoalsGrowthHistologicHistologyIndividualKRAS2 geneLabelLaboratoriesLinkLysineMalignant NeoplasmsMalignant neoplasm of lungManipulative TherapiesMass Spectrum AnalysisMeasuresMediatingMedicineMethodologyMethodsModelingMonitorNon-Small-Cell Lung CarcinomaOperative Surgical ProceduresPathogenesisPathway interactionsPeptidesPerformancePhenotypePost-Translational Protein ProcessingProcessPropertyProtein KinaseProteinsProteomicsRNA InterferenceReporterReportingResistanceRoleSamplingSignal PathwaySignal TransductionSignaling ProteinSite-Directed MutagenesisSquamous CellTechnologyTestingTherapeutic InterventionTimeTumor Cell LineTumor TissueUbiquitinUbiquitinationactivity-based protein profilingbasecancer cellcancer survivalenzyme activityestablished cell linehigh rewardhigh riskinhibitor/antagonistinterestloss of functionlung small cell carcinomamass spectrometermulticatalytic endopeptidase complexmutantnovel therapeuticsprotein complexsmall moleculesmall molecule inhibitortargeted treatmenttherapy designtooltumor
中文摘要
新出现的证据表明泛素化在癌症的发病机制中重新引起了人们对设计的兴趣
英文摘要
Emerging evidence implicating ubiquitination in the pathogenesis of cancer has renewed interest in designed
therapies that manipulate protein ubiquitination. Reversible ubiquitin modification of target proteins on lysine
residues results in major changes in signaling proteins, either through degradation through the proteasome, or
by altering the activity, localization, or protein complexes. Dysregulation of protein ubiquitination has been
linked to cancer thus raising the promise that better understanding of these signaling proteins can be combined
with chemistry to create new therapeutics. A number of key pathways have been shown to be regulated by
protein ubiquitination. Based on these observations, there is increased enthusiasm for targeting proteins
affecting protein ubiquitination. Strategies include targeting components of the E1-E2-E3 cascade or targeting
deubiquitinating enzymes (DUB) that affect disease processes. A number of studies have identified potential
DUB inhibitors (DUBi) as potential targets. Chemical or genetic loss of function studies targeting USP7,
USP14, USP9X, and UCHL5 have been reported with anti-tumor properties. This project is meant to begin
studies nominating protein ubiquitination targets by focusing on developing chemical biology strategies to
profile DUB activity in cancer cells and tumor tissues, and define mechanism of action of early DUB inhibitor
compounds. We propose to use a chemical biology platform, activity-based protein profiling (ABPP), to study
the activity of DUB in lung cancer and nominate new potential targets. ABPP uses chemical probes that are
directed against the active sites of enzymes to interrogate the functional state of enzymes in biological
samples. These activity-based probes have two critical elements: (i) a group that reacts with enzymes and
covalently labels their active sites and (ii) a reporter tag that allows for the detection or enrichment of the
modified enzymes for detection using MS approaches. Preliminary data with DUB ABPP probes demonstrates
feasibility of using this technology to profile DUB and the effects of DUBi in lung cancer cells. Aim 1 will
characterize DUB proteins in lung cancer cell lines and tumors using ABPP. DUB probes will be used to
characterize DUB signaling in multiple histological subtypes of lung cancer, including adenocarcinoma,
squamous cell, and small cell. Tumor tissues taken at the time of surgical resection and established cell lines
will be profiled and annotated to established DUB signaling pathways. Aim 2 will interrogate the functional
significance of discovered DUB proteins identified using ABPP to identify important targets that mediate lung
cancer viability. The first approach is a candidate approach, where DUB identified using ABPP will be
examined for their role in promoting lung cancer growth and survival using RNA interference and small
molecule inhibitors in cell line models. The second approach is to identify “driver” DUB using a target-agnostic
phenotypic screen of DUBi with target identification using ABPP. Changes in cell viability induced by DUBi in
lung cancer cell lines will be used alongside competitive DUB profiling to nominate & validate targets.
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