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 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 inhibitors
2021
BET 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 knockoutCells
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
Hijacking 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
2014
Targeted protein destabilization reveals an estrogen-mediated ER stress response
Raina K, Noblin DJ, Serebrenik YV, Adams A, Zhao C, Crews CM. Targeted protein destabilization reveals an estrogen-mediated ER stress response. Nature Chemical Biology 2014, 10: 957-962. PMID: 25242550, PMCID: PMC4324732, DOI: 10.1038/nchembio.1638.Peer-Reviewed Original Research
2000
The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses
Schwarz K, de Giuli R, Schmidtke G, Kostka S, van den Broek M, Kim K, Crews C, Kraft R, Groettrup M. The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses. The Journal Of Immunology 2000, 164: 6147-6157. PMID: 10843664, PMCID: PMC2507740, DOI: 10.4049/jimmunol.164.12.6147.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAmino Acid SequenceAnimalsAntigen PresentationAntigens, ViralApoptosisCell DivisionCell LineCysteine EndopeptidasesCysteine Proteinase InhibitorsDose-Response Relationship, ImmunologicDown-RegulationGlycoproteinsHumansHybridomasHydrolysisLymphocyte ActivationLymphocytic choriomeningitis virusMiceMice, Inbred BALB CMice, Inbred C57BLMolecular Sequence DataMultienzyme ComplexesNucleoproteinsOligopeptidesPeptide FragmentsProteasome Endopeptidase ComplexT-Lymphocytes, CytotoxicTumor Cells, CulturedUbiquitinsUp-RegulationViral ProteinsConceptsAg presentationProteasome inhibitor lactacystinCellular proliferationProteasome activitySelective inhibitionMHC class IDose-dependent mannerTransplant rejectionAutoimmune diseasesMouse CMVAntigen presentationMost MHC class INontoxic dosesChymotrypsin-like activityClass ISelective proteasome inhibitor lactacystinApoptosis inductionMicroM lactacystinViral proteinsPresentationInhibitionComplete inhibitionLactacystinVivoProliferation
1999
Eponemycin exerts its antitumor effect through the inhibition of proteasome function.
Meng L, Kwok BH, Sin N, Crews CM. Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Research 1999, 59: 2798-801. PMID: 10383134.Peer-Reviewed Original ResearchConceptsProteasome inhibitionCyclin-dependent kinase inhibitorNovel chemotherapeutic strategiesPharmacological interventionsAntitumor effectsPossible cancer therapySubunits LMP2Chemotherapeutic strategiesKinase inhibitorsCellular morphological changesCell cycle progressionCancer therapyCycle progressionInhibitionProteasome functionMorphological changesKey regulatory proteinsProteasomal subunitsTherapy