grant
KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition
Organization UNIV OF NORTH CAROLINA CHAPEL HILLLocation CHAPEL HILL, UNITED STATESPosted 1 Mar 2023Deadline 29 Feb 2028
NIHUS FederalResearch GrantFY20253-D3-Dimensional3DAccelerationAcrylamidesAddressAffectAffinityAssayBaptist ChurchBaptistsBindingBioassayBiochemicalBiologicalBiological AssayBody TissuesC-K-RASCancer cell lineCancersCell BodyCell Communication and SignalingCell Culture TechniquesCell LineCell SignalingCell membraneCellLineCellsCellular ExpansionCellular GrowthChemicalsChronicClinicalClinical TrialsClosure by LigationComplexComprehensive Cancer CenterComputer AnalysisComputer ModelsComputerized ModelsCrystallographiesCrystallographyCysteineCytoplasmic MembraneDNA mutationDataDevelopmentDrug DesignDrugsEnvironmentExhibitsFDA approvedFluorescenceFoundationsFrequenciesFutureGene FrequencyGeneticGenetic ChangeGenetic defectGenetic mutationGoalsGuanine NucleotidesGuanosine PhosphatesH-rasH-ras GeneH-ras OncogeneH2O2HRASHRAS geneHRAS1Half-CystineHarvey Rat Sarcoma Viral Oncogene HomologHumanHydrogen PeroxideHydroperoxideIn SituIn VitroIntracellular Communication and SignalingIsoformsK-RAS2AK-RAS2BK-RasK-Ras 2AK-Ras-2 OncogeneKRASKRAS driven oncogenesisKRAS oncogenesisKRAS(G12D)KRAS-driven tumorigenesisKRAS-mediated tumorigenesisKRAS2KRAS2 geneKRASG12DKi-RASKineticsKnowledgeL-CysteineLigandsLigationLocationLung NeoplasmsLung TumorMalignant NeoplasmsMalignant TumorMalignant Tumor of the LungMalignant neoplasm of lungMeasuresMedicationMedicineMethodsModelingModern ManModificationMolecular ConfigurationMolecular ConformationMolecular Dynamics SimulationMolecular InteractionMolecular StereochemistryMutateMutationNGS MethodNGS systemNSCLCNSCLC - Non-Small Cell Lung CancerNon-Small Cell Lung CancerNon-Small-Cell Lung CarcinomaNucleotidesOncogene K-RasOncogenesisOncogenicOperative ProceduresOperative Surgical ProceduresOrganoidsOutputOxidantsOxidation-ReductionOxidizing AgentsPathologicPatient CarePatient Care DeliveryPatientsPharmaceutical PreparationsPhysiologicPhysiologicalPlasma MembranePositionPositioning AttributePredispositionProductionPropertyProtein IsoformsProteinsPublicationsPulmonary CancerPulmonary NeoplasmsPulmonary malignant NeoplasmRAS genesRASH1RASK2ReactionRecombinant ProteinsRedoxResearch SpecimenSamplingScientific PublicationSeriesSignal TransductionSignal Transduction SystemsSignalingSiteSmokingSpecimenSpectroscopySpectrum AnalysesSpectrum AnalysisStrains Cell LinesSulfinic AcidsSurgicalSurgical InterventionsSurgical ProcedureSusceptibilitySystemTechnologyTestingTherapeuticTimeTissuesTreatment EfficacyTumor TissueWorkadductallelic frequencybench bed sidebench bedsidebench to bed sidebench to bedsidebench to clinicbench to clinical practicebiologicbiological signal transductioncare for patientscare of patientscaring for patientscell culturecell culturescell growthclinical developmentclinical efficacycold temperaturecomputational analysescomputational analysiscomputational modelingcomputational modelscomputer analysescomputer based modelscomputerized modelingconformationconformationalconformational stateconformationallyconformationscovalent bondcultured cell linedevelop therapydevelopmentaldosagedrug discoverydrug/agentelectron acceptorexperimentexperimental researchexperimental studyexperimentsgenome mutationimprovedinhibitorintervention developmentintervention efficacylow temperaturelung cancerlung cancer cellmalignancymolecular dynamicsmutantneoplasm/cancernew approachesnext gen sequencingnext generation sequencingnextgen sequencingnovel approachesnovel strategiesnovel strategyoncogenic KRASoxidationoxidation reduction reactionplasmalemmapre-clinical efficacypreclinical efficacypreventpreventingras Gene Productsras Proteinsresistance mechanismresistance to therapyresistant mechanismresistant to therapyresponseresponse to therapyresponse to treatmentscaffoldscaffoldingspatial and temporalspatial temporalspatiotemporalsurgerytargeted drug therapytargeted drug treatmentstargeted therapeutictargeted therapeutic agentstargeted therapytargeted treatmenttherapeutic efficacytherapeutic resistancetherapeutic responsetherapy developmenttherapy efficacytherapy resistanttherapy responsethioetherthree dimensionaltreatment developmenttreatment resistancetreatment responsetreatment responsivenesstumortumorigenesisv-Ha-RAS Harvey Rat Sarcoma Viral Oncogene Homologv-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
Description preview
ABSTRACT
Inhibition of oncogenic KRAS is a highly pursued goal in drug discovery efforts, as RAS mutations are found in
~25% of human cancers. One key oncogenic KRAS mutation (KRASG12C) contains a reactive cysteine at a
hotspot location, is the fourth most prevalent mutation in KRAS-driven tumors and is found at particularly high
frequency (40% of…
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