2024
BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer
Liu N, Wang S, Li M, Zhao N, Wang D, Zhang R, Yu M, Zhao L, Zhang S, Han F, Zhao Y, Liu Q. BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer. Pharmacological Research 2024, 208: 107377. PMID: 39209080, DOI: 10.1016/j.phrs.2024.107377.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBromodomain Containing ProteinsCell Cycle ProteinsCell Line, TumorCell ProliferationE2F Transcription FactorsE2F1 Transcription FactorE2F3 Transcription FactorEarly Growth Response Protein 1FemaleGene Expression Regulation, NeoplasticHumansMediator Complex Subunit 1MiceMice, NudeTranscription FactorsTranscription, GeneticTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerBET proteinsRNA polymerase IIBET bromodomainsInhibiting BET proteinsInhibition of cell growthBET degradersBreast cancerPolymerase IIFamily proteinsCell proliferation rate in vitroIncreased Egr1 expressionProliferation rate in vitroBRD4 depletionLysine residuesSeptinE2F1Cell growthRate in vitroExtraterminal domainAntiproliferative activityBET inhibitionProteinEGR1 expressionCell proliferation
2017
BET inhibitors: a novel epigenetic approach
Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Annals Of Oncology 2017, 28: 1776-1787. PMID: 28838216, DOI: 10.1093/annonc/mdx157.Peer-Reviewed Original ResearchConceptsBET inhibitorsHDAC inhibitorsEpigenetic agentsExtra-terminal motif (BET) proteinsImmune checkpoint inhibitorsEarly clinical trialsNovel epigenetic approachHistone deacetylaseZeste homolog 2BET proteinsMonotherapy activityCheckpoint inhibitorsTargeted agentsPreclinical dataClinical trialsDrug classesDrug combinationsSingle agentSolid tumorsPreclinical researchTumor cellsHomolog 2Lysine-specific demethylase 1Anticancer therapyInhibitorsBET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice
Cheung K, Lu G, Sharma R, Vincek A, Zhang R, Plotnikov A, Zhang F, Zhang Q, Ju Y, Hu Y, Zhao L, Han X, Meslamani J, Xu F, Jaganathan A, Shen T, Zhu H, Rusinova E, Zeng L, Zhou J, Yang J, Peng L, Ohlmeyer M, Walsh M, Zhang D, Xiong H, Zhou M. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 2952-2957. PMID: 28265070, PMCID: PMC5358349, DOI: 10.1073/pnas.1615601114.Peer-Reviewed Original ResearchConceptsBET proteinsActive RNA polymerase IITh17 cell differentiationProteins regulate gene transcriptionRecruitment of P-TEFbAcetyl-lysine bindingRNA polymerase IICell differentiationInflammatory disordersMature T helper cellsNaive CD4<sup>+</sup> T cellsCD4<sup>+</sup> T cellsDifferentiation of naive CD4<sup>+</sup> T cellsBlocking Th17-cell differentiationEpigenetic drug targetsT-cell transfer-induced colitisBromodomains of BET proteinsPolymerase IITreatment of inflammatory bowel diseaseT helper cellsTranscription elongationT helper 17Housekeeping genesGene locusDifferentiation of Th17Novel 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
2016
Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells
Sun B, Fiskus W, Zhang L, Raina K, Coleman K, Winkler J, Qian Y, Crew A, Shen A, Saenz D, Mill C, Wang M, Crews C, Bhalla K. Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells. Blood 2016, 128: 1058. DOI: 10.1182/blood.v128.22.1058.1058.Peer-Reviewed Original ResearchTarget gene expressionBruton's tyrosine kinaseC-MycARV-825Transcription factorsPrimary MCL cellsTranscriptional activityGene expressionTyrosine kinaseBcl-xLE3 ubiquitin ligase activityMCL cellsUbiquitin ligase activityHuman mantle cell lymphoma cellsB-cell receptor signalingCell receptor signalingBinding of BRD4Regulation of mRNAInk4a/ArfAcetylated chromatinCopy number gainsLigase activityHematopoietic progenitor cellsBET proteinsBETi treatment
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