Featured Publications
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem GM, Smith BE, Lai AC, Jaime-Figueroa S, McQuaid DC, Bondeson DP, Toure M, Dong H, Qian Y, Wang J, Crew AP, Hines J, Crews CM. The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chemical Biology 2017, 25: 67-77.e3. PMID: 29129716, PMCID: PMC5831399, DOI: 10.1016/j.chembiol.2017.09.009.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesProtein familyProtein degradationTyrosine kinaseDownstream signaling responseTargeted Protein DegradationDevelopment of PROTACsTargeted degradationEndogenous proteinsSignaling responseChimera technologyCell proliferationPROTACsPROTAC technologyKinaseKinase inhibitorsLigand showAdvantages of degradationReceptor tyrosine kinase inhibitorsTyrosine kinase inhibitorsInhibitionDegradationFamilyPowerful toolProteolysisInduced 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 potencyModular PROTAC Design for the Degradation of Oncogenic BCR‐ABL
Lai AC, Toure M, Hellerschmied D, Salami J, Jaime‐Figueroa S, Ko E, Hines J, Crews CM. Modular PROTAC Design for the Degradation of Oncogenic BCR‐ABL. Angewandte Chemie International Edition 2015, 55: 807-810. PMID: 26593377, PMCID: PMC4733637, DOI: 10.1002/anie.201507634.Peer-Reviewed Original ResearchCatalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson DP, Mares A, Smith IE, Ko E, Campos S, Miah AH, Mulholland KE, Routly N, Buckley DL, Gustafson JL, Zinn N, Grandi P, Shimamura S, Bergamini G, Faelth-Savitski M, Bantscheff M, Cox C, Gordon DA, Willard RR, Flanagan JJ, Casillas LN, Votta BJ, den Besten W, Famm K, Kruidenier L, Carter PS, Harling JD, Churcher I, Crews CM. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nature Chemical Biology 2015, 11: 611-617. PMID: 26075522, PMCID: PMC4629852, DOI: 10.1038/nchembio.1858.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBinding SitesBiocatalysisBreast NeoplasmsFemaleHumansMCF-7 CellsMiceModels, MolecularMolecular Targeted TherapyNeoplasm ProteinsNeoplasm TransplantationProteasome Endopeptidase ComplexProtein BindingProteolysisReceptor-Interacting Protein Serine-Threonine Kinase 2Receptors, EstrogenSmall Molecule LibrariesUbiquitinUbiquitinationVon Hippel-Lindau Tumor Suppressor ProteinChemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation
Schneekloth JS, Fonseca FN, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K, Crews CM. Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. Journal Of The American Chemical Society 2004, 126: 3748-3754. PMID: 15038727, DOI: 10.1021/ja039025z.Peer-Reviewed Original ResearchConceptsGreen fluorescent proteinProtein functionCell biological questionsGenetic model systemUbiquitin-proteasome pathwayChemical knockoutTargeted degradationBiological questionsProtein degradationGenetic strategiesGenetic controlGenetic lossTarget proteinsFluorescent proteinChimeric moleculesCultured cellsFKBP12 ligandsProteinProtein levelsModel systemWestern blotGeneral strategyFunction analysisVivo examplesFluorometric analysis
2024
Development of Ligands and Degraders Targeting MAGE-A3
Li K, Krone M, Butrin A, Bond M, Linhares B, Crews C. Development of Ligands and Degraders Targeting MAGE-A3. Journal Of The American Chemical Society 2024, 146: 24884-24891. PMID: 39190582, DOI: 10.1021/jacs.4c05393.Peer-Reviewed Original ResearchDNA-encoded librariesSmall molecule ligandsDevelopment of ligandsE3 ligase complexCocrystal structureChemical matterLigandPROTAC moleculesSmall moleculesLigase complexTargeted protein degradationMAGE-A3Substrate recognition moduleType I MAGEsRING E3 ligasesMoleculesCancer-selective expressionDimer interfaceImprove immunotherapy outcomesIncreased antigen presentationHigh tumor gradeE3 ligaseComplexBiochemical functionsCancer cell surfaceRegulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies
Raina K, Forbes C, Stronk R, Rappi J, Eastman K, Zaware N, Yu X, Li H, Bhardwaj A, Gerritz S, Forgione M, Hundt A, King M, Posner Z, Correia A, McGovern A, Puleo D, Chenard R, Mousseau J, Vergara J, Garvin E, Macaluso J, Martin M, Bassoli K, Jones K, Garcia M, Howard K, Yaggi M, Smith L, Chen J, Mayfield A, De Leon C, Hines J, Kayser-Bricker K, Crews C. Regulated induced proximity targeting chimeras—RIPTACs—A heterobifunctional small molecule strategy for cancer selective therapies. Cell Chemical Biology 2024, 31: 1490-1502.e42. PMID: 39116881, PMCID: PMC11371387, DOI: 10.1016/j.chembiol.2024.07.005.Peer-Reviewed Original ResearchProtein-protein interactionsTarget proteinsTernary complexChemical biology studiesExpressed intracellular proteinStable ternary complexAnti-proliferative responseEssential proteinsProtein proximityEffector ligandsIntracellular proteinsCDK inhibitorsTarget-expressing cellsHeterobifunctional small moleculesSmall moleculesCell survivalTumor cellsTherapeutic modalitiesProteinSelective therapySmall molecule strategiesLigandBiological studiesEGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling
Hu Z, Chen P, Li W, Krone M, Zheng S, Saarbach J, Velasco I, Hines J, Liu Y, Crews C. EGFR targeting PhosTACs as a dual inhibitory approach reveals differential downstream signaling. Science Advances 2024, 10: eadj7251. PMID: 38536914, PMCID: PMC10971414, DOI: 10.1126/sciadv.adj7251.Peer-Reviewed Original ResearchConceptsInhibit cancer cell viabilityProteome-wide levelCancer cell viabilityDifferential signaling pathwaysPhosphoproteomic approachTyrosine dephosphorylationProtein dephosphorylationSignal transductionActivating dephosphorylationInduce apoptosisReceptor tyrosine kinase inhibitorsRTK activationSignaling pathwayInhibition of kinasesDephosphorylationEpidermal growth factor receptorGrowth factor receptorCell viabilityFactor receptorInhibitory approachesTyrosineTyrosine kinase inhibitorsInhibitory effectInhibitory potentialKinase inhibitorsDevelopment of a Small Molecule Downmodulator for the Transcription Factor Brachyury
Chase D, Bebenek A, Nie P, Jaime‐Figueroa S, Butrin A, Castro D, Hines J, Linhares B, Crews C. Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury. Angewandte Chemie International Edition 2024, 63: e202316496. PMID: 38348945, DOI: 10.1002/anie.202316496.Peer-Reviewed Original ResearchStructure-based drug design approachX-ray crystallographyDrug design approachMass spectrometryFDA-approved kinase inhibitorsX-raySmall moleculesChordoma cellsCrystallographyTumor cell growthCompoundsChordoma cell linesMoleculesChordoma growthOncogenic transcription factorKinase inhibitorsTranscription factorsDevelopment of a Small Molecule Downmodulator for the Transcription Factor Brachyury
Chase D, Bebenek A, Nie P, Jaime‐Figueroa S, Butrin A, Castro D, Hines J, Linhares B, Crews C. Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury. Angewandte Chemie 2024, 136 DOI: 10.1002/ange.202316496.Peer-Reviewed Original Research
2023
An oral androgen receptor RIPTAC for prostate cancer.
Raina K, Eastman K, Yu X, Forbes C, Jones K, Mousseau J, Li H, Kayser-Bricker K, Crews C. An oral androgen receptor RIPTAC for prostate cancer. Journal Of Clinical Oncology 2023, 41: 184-184. DOI: 10.1200/jco.2023.41.6_suppl.184.Peer-Reviewed Original ResearchPCa cell linesAR expressionProstate cancerAR-positive cellsCastration-resistant settingLow oral doseProstate cancer modelTumor growth inhibitionProstate cancer cellsCell linesEfficacious exposureVCaP xenograftsOral dosePreclinical dataOral dosingLow nM concentrationsTumor-specific inhibitionCancer modelPharmacokinetic propertiesNormal tissuesOral bioavailabilitySignaling InhibitorsToxicology studiesAR geneCancer cellsProtein 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 evaluationTargeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality
Hu Z, Chen P, Li W, Douglas T, Hines J, Liu Y, Crews C. Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality. Journal Of The American Chemical Society 2023, 145: 4045-4055. PMID: 36753634, DOI: 10.1021/jacs.2c11706.Peer-Reviewed Original ResearchProtein tauTau dephosphorylationDisease-modifying therapiesMicrotubule-associated protein tauTau phosphorylation levelsImportant pathological roleTherapeutic modalitiesTau phosphorylationAlzheimer's diseaseTau proteinTherapeutic potentialPathological roleKinase inhibitorsEnhanced downregulationLimited benefitPhosphorylation levelsTauTauopathiesDiseaseCurrent strategiesTau phosphataseLife mimics art
Venkatachalapathy M, Crews C. Life mimics art. Cell Research 2023, 33: 267-268. PMID: 36646761, PMCID: PMC10066185, DOI: 10.1038/s41422-022-00765-0.Peer-Reviewed Original Research
2022
OligoTRAFTACs: A generalizable method for transcription factor degradation
Samarasinghe KTG, An E, Genuth MA, Chu L, Holley SA, Crews CM. OligoTRAFTACs: A generalizable method for transcription factor degradation. RSC Chemical Biology 2022, 3: 1144-1153. PMID: 36128504, PMCID: PMC9428672, DOI: 10.1039/d2cb00138a.Peer-Reviewed Original ResearchTranscription factorsOncogenic transcription factorGene expression circuitryTranscription factor degradationDNA binding abilityChordoma cell linesProteasomal degradationProteasomal pathwayZebrafish experimentsC-MycGeneralizable platformKey playersCell linesBrachyurySmall moleculesFactor degradationBinding abilityGeneralizable methodDegradationChimerasPathwayOligonucleotidePocketFirst generationTargeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC
Swartzel JC, Bond MJ, Pintado-Urbanc AP, Daftary M, Krone MW, Douglas T, Carder EJ, Zimmer JT, Maeda T, Simon MD, Crews CM. Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC. ACS Chemical Biology 2022, 17: 1789-1798. PMID: 35749470, PMCID: PMC10367122, DOI: 10.1021/acschembio.2c00145.Peer-Reviewed Original ResearchPROTACs: past, present and future
Li K, Crews CM. PROTACs: past, present and future. Chemical Society Reviews 2022, 51: 5214-5236. PMID: 35671157, PMCID: PMC10237031, DOI: 10.1039/d2cs00193d.Peer-Reviewed Original ResearchConceptsProtein of interestProteolysis-targeting chimerasUbiquitin-proteasome systemE3 ubiquitin ligaseSmall molecule inhibitorsUbiquitin ligaseNonenzymatic functionProtein degradationHeterobifunctional moleculesDrug resistance mechanismsMolecule inhibitorsSubsequent degradationUbiquitinationLigasePromising therapeuticsProteinChimerasPotential toxicityDegradationMechanismHijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Nalawansha DA, Li K, Hines J, Crews CM. Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation. Journal Of The American Chemical Society 2022, 144: 5594-5605. PMID: 35311258, PMCID: PMC10331457, DOI: 10.1021/jacs.2c00874.Peer-Reviewed Original ResearchConceptsE3 ligase complexLigase complexProtein degradationReader proteinsMethyl readersE3 ligaseProteasomal degradationPROTAC designProtein levelsProteinLigand pairsDrug discovery paradigmPROTACsNatural mechanismGeneralizable approachComplexesDiscovery paradigmCUL4BRD2DegradationLigaseL3MBTL3FKBP12Biological evaluationPromising strategyPROTAC 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
Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
Chen PH, Hu Z, An E, Okeke I, Zheng S, Luo X, Gong A, Jaime-Figueroa S, Crews CM. Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs). ACS Chemical Biology 2021, 16: 2808-2815. PMID: 34780684, PMCID: PMC10437008, DOI: 10.1021/acschembio.1c00693.Peer-Reviewed Original ResearchConceptsSer/Thr phosphataseChemical biology approachPP2A holoenzymeProtein dephosphorylationBiology approachProtein substratesTranscriptional activationProtein phosphorylationCatalytic subunitCell biologyReporter geneProtein activityRetinoblastoma proteinOff-target effectsCritical proteinsDephosphorylationTernary complexPhosphorylationKinase inhibitorsFOXO3aPROTACsProteinChimerasPhosphataseDrug resistance