Featured Publications
Induced protein degradation: an emerging drug discovery paradigm
Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nature Reviews Drug Discovery 2016, 16: 101-114. PMID: 27885283, PMCID: PMC5684876, DOI: 10.1038/nrd.2016.211.Peer-Reviewed Original ResearchConceptsProteolysis-targeting chimaerasProtein degradationUndruggable proteomeTarget protein degradationDifferent E3 ligasesInhibitor-based approachE3 ligasesDrug discovery platformProtein targetsProteomeDiscovery platformProtein expressionDrug discovery paradigmInhibition approachCell culturesDiscovery paradigmLigasesExact mechanismDegradationMouse modelDegradersProteinChimaerasPicomolar potency
2023
Protein degraders enter the clinic — a new approach to cancer therapy
Chirnomas D, Hornberger K, Crews C. Protein degraders enter the clinic — a new approach to cancer therapy. Nature Reviews Clinical Oncology 2023, 20: 265-278. PMID: 36781982, DOI: 10.1038/s41571-023-00736-3.Peer-Reviewed Original ResearchConceptsPhase III trialsCancer therapyNovel therapeutic modalitiesIII trialsClinical trialsPreclinical modelsClinical studiesTherapeutic modalitiesPharmacokinetic dataSmall molecule inhibitorsDisease pathogenesisClinical testingTumor typesDrug concentrationsPreclinical researchCancer treatmentPhase IFirst safetyUbiquitin-proteasome systemPatientsProtein degradersTherapyMore evidenceTrialsRigorous evaluation
2022
PROTAC targeted protein degraders: the past is prologue
Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery 2022, 21: 181-200. PMID: 35042991, PMCID: PMC8765495, DOI: 10.1038/s41573-021-00371-6.Peer-Reviewed Original Research
2021
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
Hu Z, Crews CM. Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic. ChemBioChem 2021, 23: e202100270. PMID: 34494353, PMCID: PMC9395155, DOI: 10.1002/cbic.202100270.Peer-Reviewed Original ResearchTargeted protein degradation: A promise for undruggable proteins
Samarasinghe KTG, Crews CM. Targeted protein degradation: A promise for undruggable proteins. Cell Chemical Biology 2021, 28: 934-951. PMID: 34004187, PMCID: PMC8286327, DOI: 10.1016/j.chembiol.2021.04.011.Peer-Reviewed Original ResearchConceptsProteolysis Targeting ChimerasUndruggable proteinsDisease-causing proteinsProtein degradation strategiesProteostasis mechanismsProtein homeostasisTranscription factorsProtein degradationHeterobifunctional moleculesProteinDegradation strategiesDisease initiationBiological effectsProteostasisDegradationPotential therapeutic modalityHomeostasisChimerasCellsAccumulationBET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma
Fiskus W, Mill CP, Perera D, Birdwell C, Deng Q, Yang H, Lara BH, Jain N, Burger J, Ferrajoli A, Davis JA, Saenz DT, Jin W, Coarfa C, Crews CM, Green MR, Khoury JD, Bhalla KN. BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma. Leukemia 2021, 35: 2621-2634. PMID: 33654205, PMCID: PMC8410602, DOI: 10.1038/s41375-021-01181-w.Peer-Reviewed Original ResearchMeSH KeywordsAdenineAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBiomarkers, TumorBridged Bicyclo Compounds, HeterocyclicCell ProliferationCell Transformation, NeoplasticGene Expression Regulation, NeoplasticHumansLymphoma, Large B-Cell, DiffuseMicePiperidinesProteinsProteolysisSulfonamidesTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsLarge B-cell lymphomaB-cell lymphomaRichter transformationBET protein inhibitorLymphoma burdenImproved survivalCombination therapyC-Myc levelsEffective therapyNovel therapiesCell lymphomaXenograft modelProtein inhibitorTherapyBET inhibitorsProtein expressionCLLGenetic alterationsLymphomaInhibitorsIRF4Single-cell RNA-seqHuman modelCRISPR knockoutCellsMajor advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
Alabi SB, Crews C. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. Journal Of Biological Chemistry 2021, 296: 100647. PMID: 33839157, PMCID: PMC8131913, DOI: 10.1016/j.jbc.2021.100647.Peer-Reviewed Original ResearchConceptsProtein degradationProtein degradation pathwaysProteolysis targeting chimera (PROTAC) technologyUbiquitin-proteasome systemEndo-lysosomal pathwaySmall molecule inhibitorsDruggable spaceChemical toolsInnovative chemical toolMolecular glueChimera technologyProtein moleculesDegradation pathwayOutstanding questionsCurrent understandingMajor advancesPathwayAutophagyPROTACsDegradationCellsInhibitorsAdvances
2017
BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells
Sun B, Fiskus W, Qian Y, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Saenz DT, Mill CP, Nowak AJ, Jain N, Zhang L, Wang M, Khoury JD, Coarfa C, Crews CM, Bhalla KN. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia 2017, 32: 343-352. PMID: 28663582, DOI: 10.1038/leu.2017.207.Peer-Reviewed Original ResearchConceptsMantle cell lymphoma cellsMCL cellsCell lymphoma cellsARV-825ARV-771Lymphoma cellsGreater survival improvementSuperior preclinical activityCDK4/6 inhibitor palbociclibNuclear factor-κB (NF-κB) target genesExtraterminal protein inhibitorSurvival improvementInhibitor palbociclibPreclinical activityCDKN1A/p21Inhibitor treatmentSuperior pharmacological propertiesVivo growthCyclin D1Pharmacological propertiesProtein expressionMore apoptosisVivo evaluationIncomplete inhibitionC-Myc
2016
Small‐Molecule PROTACS: New Approaches to Protein Degradation
Toure M, Crews CM. Small‐Molecule PROTACS: New Approaches to Protein Degradation. Angewandte Chemie International Edition 2016, 55: 1966-1973. PMID: 26756721, DOI: 10.1002/anie.201507978.Peer-Reviewed Original ResearchConceptsProteolysis-targeting chimerasProtein degradationCellular quality control machineryQuality control machineryNovel catalytic mechanismInhibitor-based approachDrug target spaceProtein functionControl machineryProtein classesProtein destructionCatalytic mechanismCellular levelActive siteTherapeutic potentialOff-target side effectsMachineryRecent reportsChimerasDegradationRecruitmentTherapeuticsInhibition
2014
Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System
Buckley DL, Crews CM. Small‐Molecule Control of Intracellular Protein Levels through Modulation of the Ubiquitin Proteasome System. Angewandte Chemie International Edition 2014, 53: 2312-2330. PMID: 24459094, PMCID: PMC4348030, DOI: 10.1002/anie.201307761.Peer-Reviewed Original ResearchConceptsSmall molecule modulatorsProtein levelsSmall-molecule probesUbiquitin-proteasome systemActivity of proteinsIntracellular protein levelsBiological probesProteasome systemProtein degradationUbiquitin-proteasomeProtein activitySmall moleculesMolecule controlDruggable targetsProteomeProteasomeTargeted fashionProteinRemaining majorityGlobal increaseProbeUPSMoleculesDegradationMultiple strategies
2010
Chemical Inducers of Targeted Protein Degradation*
Raina K, Crews CM. Chemical Inducers of Targeted Protein Degradation*. Journal Of Biological Chemistry 2010, 285: 11057-11060. PMID: 20147751, PMCID: PMC2856979, DOI: 10.1074/jbc.r109.078105.Peer-Reviewed Original ResearchConceptsProtein degradationTargeted Protein DegradationPost-translational levelSubsequent phenotypic analysisProtein functionSelective gene inactivationCellular proteinsCellular phenotypesRNA interferenceGene inactivationSpecific proteinsChemical inducersPhenotypic analysisChemical inductionGenetic mutationsProteinGenesDegradationMutationsPhenotypeDecreased productionMRNAInducerInactivationInduction
2006
Probing Protein Function with Small Molecules
Gough JD, Crews CM. Probing Protein Function with Small Molecules. Ernst Schering Foundation Symposium Proceedings 2006, 58: 61-74. PMID: 16708999, DOI: 10.1007/978-3-540-37635-4_5.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiotinylationCombinatorial Chemistry TechniquesDrug DesignDrug Evaluation, PreclinicalGenomicsGreen Fluorescent ProteinsHumansKetonesModels, ChemicalMolecular Probe TechniquesNanotechnologyOligopeptidesPhosphorylationProtein BindingProteinsReceptors, AndrogenRecombinant Fusion ProteinsSerineSesquiterpenesSignal TransductionUbiquitin-Protein Ligases
2003
Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro
Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S, Crews CM, Mundy GR. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. Journal Of Clinical Investigation 2003, 111: 1771-1782. PMID: 12782679, PMCID: PMC156102, DOI: 10.1172/jci16198.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, NorthernBlotting, WesternBone and BonesBone DevelopmentBone Morphogenetic Protein 2Bone Morphogenetic Protein 4Bone Morphogenetic ProteinsCarrier ProteinsCell DivisionCell LineCysteine EndopeptidasesDNADose-Response Relationship, DrugEnzyme-Linked Immunosorbent AssayGenetic VectorsHumansLuciferasesMiceMice, Inbred ICRMultienzyme ComplexesOrgan Culture TechniquesOsteoblastsPromoter Regions, GeneticProteasome Endopeptidase ComplexProteinsRNA, MessengerSkullTranscription, GeneticTransfectionTransforming Growth Factor betaConceptsUbiquitin-proteasome pathwayBMP-4BMP-2Osteoblast differentiationBMP-6 mRNA expressionUbiquitin-proteasome machineryEffect of nogginCatalytic beta subunitsProteasome inhibitorsBMP-2 gene expressionBone morphogenetic protein-2Drosophila homologueMorphogenetic protein-2Gli3 proteinGene expressionBeta subunitProteolytic processingProtein 2Bone formationDifferent inhibitorsEndogenous inhibitorOsteoblastic cellsProteasomeNogginInhibitor-1
1992
The Primary Structure of MEK, a Protein Kinase that Phosphorylates the ERK Gene Product
Crews C, Alessandrini A, Erikson R. The Primary Structure of MEK, a Protein Kinase that Phosphorylates the ERK Gene Product. Science 1992, 258: 478-480. PMID: 1411546, DOI: 10.1126/science.1411546.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceCalcium-Calmodulin-Dependent Protein KinasesGene ExpressionMAP Kinase Kinase 1MiceMitogen-Activated Protein Kinase KinasesMolecular Sequence DataPhosphorylationProtein KinasesProtein Serine-Threonine KinasesProteinsProtein-Tyrosine KinasesRNA, MessengerSequence AlignmentConceptsExtracellular signal-regulated kinaseProtein kinaseMAP kinaseGene productsCritical protein kinaseSignal-regulated kinaseComplementary DNA sequenceMEK genesExtracellular signalsERK kinaseMultiple biochemical signalsDNA sequencesBiochemical signalsPrimary structureKinaseAmino acidsEnzymatic activityGenesMurine brainSequenceSchizosaccharomycesMEK1MEKThreonineProtein