Featured Publications
Modular 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 Research
2024
EGFR 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 ResearchMeSH KeywordsApoptosisCell Line, TumorErbB ReceptorsHumansPhosphorylationProteolysis Targeting ChimeraSignal TransductionTyrosineConceptsInhibit 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 inhibitors
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 conformationPatientsV600
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-MycNovel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells
Saenz DT, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Mill CP, Sun B, Qiu P, Kadia TM, Pemmaraju N, DiNardo C, Kim MS, Nowak AJ, Coarfa C, Crews CM, Verstovsek S, Bhalla KN. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 2017, 31: 1951-1961. PMID: 28042144, PMCID: PMC5537055, DOI: 10.1038/leu.2016.393.Peer-Reviewed Original ResearchConceptsBET protein inhibitorARV-825Messenger RNAReverse phase protein arrayPhase protein arrayRNA-seqHematopoietic progenitor cellsNormal hematopoietic progenitor cellsBET proteinsE3 ubiquitin ligase cereblonLevels of p21Extraterminal (BET) proteinsBcl-xLBromodomain inhibitorsC-MycJAK inhibitor ruxolitinibBRD4Protein arraysProgenitor cellsProtein expressionHEL92.1.7 cellsImproved survivalLeukemia burdenNSG miceProfound depletion
2015
Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Gustafson JL, Neklesa TK, Cox CS, Roth AG, Buckley DL, Tae HS, Sundberg TB, Stagg DB, Hines J, McDonnell DP, Norris JD, Crews CM. Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angewandte Chemie International Edition 2015, 54: 9659-9662. PMID: 26083457, PMCID: PMC4547777, DOI: 10.1002/anie.201503720.Peer-Reviewed Original ResearchMeSH KeywordsAndrogen Receptor AntagonistsAntineoplastic AgentsBenzamidesCell Line, TumorCell ProliferationDrug Resistance, NeoplasmHumansHydrophobic and Hydrophilic InteractionsMaleNitrilesPhenylthiohydantoinPoint MutationProstateProstatic NeoplasmsProteolysisReceptors, AndrogenSmall Molecule LibrariesConceptsSelective androgen receptor degradersAndrogen receptorAR mutationsAndrogen-dependent prostate cancer cell lineSecond-generation AR antagonistsAR degradationProstate tumor cell proliferationProstate cancer cell linesAR target genesTumor cell proliferationAntitumor chemotherapeutic agentsCancer cell linesAR antagonistsChemotherapeutic agentsCell proliferationAR ligandsCell linesAntagonistTumor strategyResistance mechanismsReceptorsRecent studiesProliferationTarget genesDependent transcriptionHijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, Hines J, Winkler JD, Crew AP, Coleman K, Crews CM. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Cell Chemical Biology 2015, 22: 755-763. PMID: 26051217, PMCID: PMC4475452, DOI: 10.1016/j.chembiol.2015.05.009.Peer-Reviewed Original ResearchAcetanilidesAdaptor Proteins, Signal TransducingApoptosisAzepinesCell Cycle ProteinsCell Line, TumorCell ProliferationHeterocyclic Compounds, 3-RingHumansNuclear ProteinsPeptide HydrolasesProto-Oncogene Proteins c-mycSignal TransductionThalidomideTranscription FactorsTriazolesUbiquitin-Protein Ligases
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