2018
Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
Burslem GM, Ottis P, Jaime‐Figueroa S, Morgan A, Cromm PM, Toure M, Crews C. Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships. ChemMedChem 2018, 13: 1508-1512. PMID: 29870139, PMCID: PMC6291207, DOI: 10.1002/cmdc.201800271.Peer-Reviewed Original ResearchConceptsOne-pot synthesisIMiD analoguesStructure-activity relationshipsNarrow structure-activity relationshipMultiple purification stepsEfficient synthesisStepwise routePurification stepsSynthesisAnti-proliferative activityRapid accessProtein cereblonAiolos degradationFunctionalizationAnaloguesCompoundsMoleculesDegradationHereinPurificationRouteAffinityCereblon
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