2023
An oral androgen receptor RIPTAC for prostate cancer.
Raina K, Eastman K, Yu X, Forbes C, Jones K, Mousseau J, Li H, Kayser-Bricker K, Crews C. An oral androgen receptor RIPTAC for prostate cancer. Journal Of Clinical Oncology 2023, 41: 184-184. DOI: 10.1200/jco.2023.41.6_suppl.184.Peer-Reviewed Original ResearchPCa cell linesAR expressionProstate cancerAR-positive cellsCastration-resistant settingLow oral doseProstate cancer modelTumor growth inhibitionProstate cancer cellsCell linesEfficacious exposureVCaP xenograftsOral dosePreclinical dataOral dosingLow nM concentrationsTumor-specific inhibitionCancer modelPharmacokinetic propertiesNormal tissuesOral bioavailabilitySignaling InhibitorsToxicology studiesAR geneCancer cells
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 generation
2020
Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs
Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs. ACS Central Science 2020, 6: 1367-1375. PMID: 32875077, PMCID: PMC7453568, DOI: 10.1021/acscentsci.0c00411.Peer-Reviewed Original Research
2017
BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825 Targets Both NOTCH1-MYC Regulatory Circuit and Leukemia-Microenvironment in T-ALL
Piya S, Mu H, Bhattacharya S, McQueen T, Davis R, Ruvolo V, Baran N, Qian Y, Raina K, Crews C, You M, McKay P, Konopleva M, Kantarjian H, Andreeff M, Borthakur G. BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825 Targets Both NOTCH1-MYC Regulatory Circuit and Leukemia-Microenvironment in T-ALL. Blood 2017, 130: 716. DOI: 10.1182/blood.v130.suppl_1.716.716.Peer-Reviewed Original ResearchT-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaARV-825PI3K/AktGamma-secretase inhibitorsMouse modelRelapsed T-cell acute lymphoblastic leukemiaVehicle-treated control micePatient-derived xenograft mouse modelsCell linesLow leukemia burdenCell acute lymphoblastic leukemiaReactive oxygen speciesT-cell lymphoblastic leukemiaAnti-leukemic effectsXenograft mouse modelLeukemia-stroma interactionsPDX mouse modelsBristol-Meyers SquibbG1/S cell cycle progressionPersistence of diseaseAttractive therapeutic targetIntra-cellular reactive oxygen speciesMicroenvironmental signalsAn oral androgen receptor PROTAC degrader for prostate cancer.
Neklesa T, Snyder L, Bookbinder M, Chen X, Crew A, Crews C, Dong H, Gordon D, Raina K, Rossi A, Taylor I, Vitale N, Wang J, Willard R, Zimmermann K. An oral androgen receptor PROTAC degrader for prostate cancer. Journal Of Clinical Oncology 2017, 35: 273-273. DOI: 10.1200/jco.2017.35.6_suppl.273.Peer-Reviewed Original ResearchAndrogen receptorAR degradationProstate cancerAR proteinAR target gene PSADegradation of ARCastration-resistant prostate cancerTotal androgen receptorMajority of patientsMutant AR proteinTumor growth inhibitionVivo preclinical studiesCell linesInhibits cell proliferationVCaP xenograftsMetastatic diseaseMost patientsAR pathwayElevated androgensMechanisms of resistancePreclinical studiesXenograft studiesVCaP cellsOral bioavailabilityPotent apoptosis
2016
BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825, Causes Sustained Degradation of BRD4 and Modulation of Chemokine Receptors, Cell Adhesion and Metabolic Targets in Leukemia Resulting in Profound Anti-Leukemic Effects
Piya S, Bhattacharya S, Mu H, Lorenzi P, McQueen T, Davis E, Ruvolo V, Baran N, Qian Y, Crews C, Kantarjian H, Andreeff M, Borthakur G. BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825, Causes Sustained Degradation of BRD4 and Modulation of Chemokine Receptors, Cell Adhesion and Metabolic Targets in Leukemia Resulting in Profound Anti-Leukemic Effects. Blood 2016, 128: 748. DOI: 10.1182/blood.v128.22.748.748.Peer-Reviewed Original ResearchProteolysis Targeting ChimerasARV-825Cell adhesionExtra-terminal domain (BET) familyOverexpression of PIM1Amino acid transportersDegradation of BRD4Production of ATPGene expression profilingMesenchymal stromal cellsCell linesImportant amino acidsTranscription of oncogenesBcl-2 family moleculesStroma-mediated drug resistanceWnt/β-catenin pathwayNutrient acquisitionRegulatory machineryFlow cytometryEnhancer complexTranscriptional coactivatorSmall-molecule BRD4 inhibitorsDomain familyEpigenetic eventsProteomic analysis
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 transcriptionSmall‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging
Gustafson J, Neklesa T, Cox C, Roth A, Buckley D, Tae H, Sundberg T, Stagg D, Hines J, McDonnell D, Norris J, Crews C. Small‐Molecule‐Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angewandte Chemie 2015, 127: 9795-9798. DOI: 10.1002/ange.201503720.Peer-Reviewed Original ResearchSelective 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 transcription
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