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 generationPROTACs: 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 toxicityDegradationMechanism
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 resistanceProteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation
Bond MJ, Crews CM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chemical Biology 2021, 2: 725-742. PMID: 34212149, PMCID: PMC8190915, DOI: 10.1039/d1cb00011j.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 modalityHomeostasisChimerasCellsAccumulationTargeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras
Samarasinghe KTG, Jaime-Figueroa S, Burgess M, Nalawansha DA, Dai K, Hu Z, Bebenek A, Holley SA, Crews CM. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chemical Biology 2021, 28: 648-661.e5. PMID: 33836141, PMCID: PMC8524358, DOI: 10.1016/j.chembiol.2021.03.011.Peer-Reviewed Original ResearchConceptsTranscription factorsTargeted degradationTranscription factor degradationDNA-binding proteinsMultiple signaling pathwaysGeneralizable strategyDCas9 proteinProtein familyLigandable sitesProteasomal pathwaySignaling pathwaysOverexpression of oncoproteinsAberrant activationChimeric oligonucleotideProteinChimerasFactor degradationNF-κBPathwayHaloTagDegradationBrachyuryOverexpressionOncoproteinOligonucleotide
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