Featured Publications
Catalytic 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 Protein
2022
PROTACs: 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
Mutant-selective degradation by BRAF-targeting PROTACs
Alabi S, Jaime-Figueroa S, Yao Z, Gao Y, Hines J, Samarasinghe KTG, Vogt L, Rosen N, Crews CM. Mutant-selective degradation by BRAF-targeting PROTACs. Nature Communications 2021, 12: 920. PMID: 33568647, PMCID: PMC7876048, DOI: 10.1038/s41467-021-21159-7.Peer-Reviewed Original ResearchConceptsInhibitor-based therapyBRAF inhibitor-based therapiesBRAF missense mutationsCancer cell growthBRAF V600Current treatmentNew therapiesTherapeutic windowXenograft modelBRAF mutantMutant BRAFVivo efficacyDrug modalitiesRaf family membersProteolysis targeting chimera (PROTAC) technologyTherapyBRAFMissense mutationsFamily membersBRAFWTCell growthDegree of selectivityInactivated conformationPatientsV600Major 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
2013
A Bidirectional System for the Dynamic Small Molecule Control of Intracellular Fusion Proteins
Neklesa TK, Noblin DJ, Kuzin A, Lew S, Seetharaman J, Acton TB, Kornhaber G, Xiao R, Montelione G, Tong L, Crews CM. A Bidirectional System for the Dynamic Small Molecule Control of Intracellular Fusion Proteins. ACS Chemical Biology 2013, 8: 2293-2300. PMID: 23978068, PMCID: PMC4113957, DOI: 10.1021/cb400569k.Peer-Reviewed Original ResearchConceptsSmall molecule controlProtein functionFusion proteinMolecule controlIntracellular fusion proteinOncogenic H-RasCellular protein levelsProtein of interestProtein levelsSmall-molecule screenIntracellular protein levelsDose-dependent regulationCellular transformationH-RasMolecule screenPhysiological roleProteinTherapeutic targetDose-dependent mannerHydrophobic tagUbiquitinationBidirectional controlHSP70DehalogenaseRegulation
2008
Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer
Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, Sakamoto KM. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene 2008, 27: 7201-7211. PMID: 18794799, PMCID: PMC5573236, DOI: 10.1038/onc.2008.320.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBlotting, WesternBreast NeoplasmsCell CycleCell Line, TumorCell ProliferationDihydrotestosteroneDrug Delivery SystemsEstradiolEstrogen Receptor alphaFemaleFlow CytometryHumansHypoxia-Inducible Factor 1, alpha SubunitMaleNeoplasms, Hormone-DependentProstatic NeoplasmsProteasome Endopeptidase ComplexReceptors, AndrogenReceptors, SteroidRecombinant Fusion ProteinsUbiquitinationConceptsBreast cancer cellsProstate cancer cellsCancer cellsAndrogen-dependent prostate cancer cellsHormone-dependent cell linesEstrogen-independent breast cancer cellsEstrogen-dependent breast cancer cellsHormone receptorsHormone-dependent breastG1 arrestDegradation of ERαSteroid hormone receptorsERα expressionProgesterone receptorAndrogen receptorProstate cancerEstrogen receptorCyclin D1Retinoblastoma phosphorylationReceptorsCell linesERαBreastProliferationProteasome-dependent manner