2024
Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets
Rukhlenko O, Imoto H, Tambde A, McGillycuddy A, Junk P, Tuliakova A, Kolch W, Kholodenko B. Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets. Cancers 2024, 16: 2354. PMID: 39001416, PMCID: PMC11240448, DOI: 10.3390/cancers16132354.Peer-Reviewed Original ResearchControl of cell movementCell linesCell statesLuminal BC cellsControl cell phenotypeWaddington landscapeTissue-derived cell linesCell movementOncogenic transformationSmall molecule inhibitorsSignaling nodeBC cell linesExpression profilesPerturbation datasetsNormal cell stateMolecule inhibitorsBC cellsCell phenotypeBasal BCBC subtypesBreast cancerOncogenic driversCellsCurrent biologicsBreast tissue cellsWnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications
Afroz R, Goodwin J. Wnt Signaling in Atherosclerosis: Mechanisms to Therapeutic Implications. Biomedicines 2024, 12: 276. PMID: 38397878, PMCID: PMC10886882, DOI: 10.3390/biomedicines12020276.Peer-Reviewed Original ResearchWnt pathwayWnt signalingAtherosclerosis progressionSmooth muscle cell proliferationMuscle cell proliferationPathophysiology of atherosclerosisBlock Wnt signalingDownstream signaling moleculesStages of atherosclerosis progressionPreclinical modelsMonocyte infiltrationEndothelial dysfunctionSmall molecule inhibitorsTreatment of atherosclerosisVascular inflammationTherapeutic approachesTherapeutic implicationsCo-receptorVascular diseaseAtherosclerosis developmentAtherosclerosisCell proliferationWnt ligandsMolecule inhibitorsWnt
2023
Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies
Cosgun K, Robinson M, Oulghazi S, Xu L, Xiao G, Chan L, Lee J, Kume K, Leveille E, Arce D, Khanduja D, Feldhahn N, Song J, Chan W, Chen J, Taketo M, Schjerven H, Jellusova J, Kothari S, Davids M, Müschen M. Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies. Blood 2023, 142: 2818. DOI: 10.1182/blood-2023-190522.Peer-Reviewed Original ResearchFavorable safety profileSmall molecule inhibitorsT-lymphoid malignancyΒ-catenin degradationLymphoid malignanciesΒ-cateninInteractome studiesSafety profileClinical trialsMolecule inhibitorsLow nanomolar concentrationsΒ-catenin accumulationSolid tumorsRefractory B-cell malignanciesCell deathPK/PD profilesZinc finger proteinRefractory lymphoid malignanciesChIP-seq analysisPhase 2 trialMYC target genesT-cell lymphomaColony formationRapid nuclear accumulationWnt/β-catenin pathwayComputational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies
Li Q, Robinson M, Leveille E, Zhang C, Sun R, Cheng Z, Kume K, Cosgun K, Kothari S, Khanduja D, Nakada D, Müschen M. Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies. Blood 2023, 142: 418. DOI: 10.1182/blood-2023-190269.Peer-Reviewed Original ResearchSmall molecule inhibitorsDrug discovery toolNAMPT inhibitorsCompound screenCell type-specific targetsCell linesMolecule inhibitorsPurine/pyrimidine metabolismTumor cell linesEnergy metabolismSalvage biosynthesis pathwaySolid tumor cell linesB cell developmentCellular energy metabolismB cell signalingAmino acid metabolismCell cycle arrestDiscovery toolDepletion of metabolitesBiosynthesis pathwayCompetitive fitnessRate-limiting enzymeNAMPT deletionConditional mouse modelEnergy stressNovel Causal Inference Method Estimates Treatment Effects of Contemporary Drugs in a Global Cohort of Patients with Relapsed and Refractory Mature T-Cell and NK-Cell Neoplasms
Koh M, Boussi L, Han J, Peng L, Sorial M, Eche-Ugwu I, Miranda E, Chiattone C, Stuver R, Horwitz S, Turizo M, McCabe S, Merrill M, Jacobsen E, Kim J, Kim Y, Cho J, Eipe T, Shet T, Jain H, Sengar M, Singh S, Gabler J, Koh M, Van Der Weyden C, Prince M, Hamouche R, Muradashvili T, Foss F, Gentilini M, Casadei B, Zinzani P, Okatani T, Yoshida N, Yoon S, Kim W, Panchoo G, Mohamed Z, Verburgh E, Alturas J, Al Mansour M, Ford J, Manni M, Federico M, O'Connor O, Cabrera M, Shen C, Marchi E, Shah D, Jain S. Novel Causal Inference Method Estimates Treatment Effects of Contemporary Drugs in a Global Cohort of Patients with Relapsed and Refractory Mature T-Cell and NK-Cell Neoplasms. Blood 2023, 142: 1703. DOI: 10.1182/blood-2023-185881.Peer-Reviewed Original ResearchSuperior overall survivalCytotoxic chemotherapyOverall survivalNK-cell neoplasmsBrentuximab vedotinPTCL-NOSMultivariate CoxSingle agentALK- ALCLSmall molecule inhibitorsComparable OSGlobal cohortLargest global cohortClinical trialsT cellsConcordance indexMultivariate Cox regression modelSecond-line therapyPrimary refractory patientsIndependent prognostic effectCox regression modelMolecule inhibitorsReal-world evidenceEpigenetic modifiersMature T cellsLysine Demethylation in Pathogenesis
Cao J, Yan Q. Lysine Demethylation in Pathogenesis. Advances In Experimental Medicine And Biology 2023, 1433: 1-14. PMID: 37751133, DOI: 10.1007/978-3-031-38176-8_1.ChaptersConceptsLysine demethylasesLSD1/KDM1AHistone lysine methylationHistone lysine methyltransferasesMajor epigenetic mechanismsNormal developmentNon-histone substratesSpecific small molecule inhibitorsSmall molecule inhibitorsLysine methylationLysine methyltransferasesHistone methylationHistone lysineLysine demethylationEpigenetic mechanismsDNA repairArginine residuesHuman diseasesMore subfamiliesMolecule inhibitorsLysine modificationDemethylasesMethylationTreatment of cancerEnzymePyroptosis in cardiovascular diseases: Pumping gasdermin on the fire
Yarovinsky T, Su M, Chen C, Xiang Y, Tang W, Hwa J. Pyroptosis in cardiovascular diseases: Pumping gasdermin on the fire. Seminars In Immunology 2023, 69: 101809. PMID: 37478801, PMCID: PMC10528349, DOI: 10.1016/j.smim.2023.101809.Peer-Reviewed Original ResearchConceptsPost-translational modificationsAcute cardiovascular eventsChronic cardiovascular diseaseCardiovascular diseaseSmall molecule inhibitorsPyroptosis resultsGenetic toolsGasdermin proteinsWhole organismInflammatory caspasesCardiovascular eventsCell deathMolecule inhibitorsCell typesProteolytic cleavageCellular mechanismsActivation of inflammasomesCardiovascular systemKnockout animalsAmplification of inflammationRole of pyroptosisPro-inflammatory processesDifferent cellsNovel therapeutic approachesPyroptosisScreening for small molecule inhibitors of SAH nucleosidase using an SAH riboswitch
Sadeeshkumar H, Balaji A, Sutherland A, Mootien S, Anthony K, Breaker R. Screening for small molecule inhibitors of SAH nucleosidase using an SAH riboswitch. Analytical Biochemistry 2023, 666: 115047. PMID: 36682579, PMCID: PMC11149561, DOI: 10.1016/j.ab.2023.115047.Peer-Reviewed Original ResearchConceptsHigh-throughput screenAutoinducer-2Reporter geneBacterial processesEssential bacterial processesGram-negative bacterial cellsQuorum sensing signalsΒ-galactosidase reporter geneSmall molecule inhibitorsAntibiotic drug discoveryNatural riboswitchesAntimicrobial drug developmentRNA elementsPhysiological signalingRiboswitchBacterial cellsMolecule inhibitorsS-adenosylmethionineEscherichia coliCritical functionsNew targetsGenesDrug discoverySmall moleculesPromising target
2022
PROTACs: past, present and future
Li K, Crews CM. PROTACs: past, present and future. Chemical Society Reviews 2022, 51: 5214-5236. PMID: 35671157, PMCID: PMC10237031, DOI: 10.1039/d2cs00193d.Peer-Reviewed Original ResearchConceptsProtein of interestProteolysis-targeting chimerasUbiquitin-proteasome systemE3 ubiquitin ligaseSmall molecule inhibitorsUbiquitin ligaseNonenzymatic functionProtein degradationHeterobifunctional moleculesDrug resistance mechanismsMolecule inhibitorsSubsequent degradationUbiquitinationLigasePromising therapeuticsProteinChimerasPotential toxicityDegradationMechanismA molecular beacon assay for monitoring RNA splicing
Omran QQ, Fedorova O, Liu T, Pyle AM. A molecular beacon assay for monitoring RNA splicing. Nucleic Acids Research 2022, 50: e74-e74. PMID: 35438748, PMCID: PMC9303364, DOI: 10.1093/nar/gkac242.Peer-Reviewed Original ResearchConceptsMolecular beaconsMolecular beacon assayHigher fluorescent signalHigh-throughput screening platformSmall moleculesAutocatalyzed reactionMolecular beacon approachKinetic characterizationReactionSmall molecule targetingInhibition constantsScreening platformSmall molecule inhibitorsFluorescent signalMolecule targetingMolecule inhibitorsMolecules
2021
NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021.
Zelenetz AD, Gordon LI, Chang JE, Christian B, Abramson JS, Advani RH, Bartlett NL, Budde LE, Caimi PF, De Vos S, Dholaria B, Fakhri B, Fayad LE, Glenn MJ, Habermann TM, Hernandez-Ilizaliturri F, Hsi E, Hu B, Kaminski MS, Kelsey CR, Khan N, Krivacic S, LaCasce AS, Lim M, Narkhede M, Rabinovitch R, Ramakrishnan P, Reid E, Roberts KB, Saeed H, Smith SD, Svoboda J, Swinnen LJ, Tuscano J, Vose JM, Dwyer MA, Sundar H. NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021. Journal Of The National Comprehensive Cancer Network 2021, 19: 1218-1230. PMID: 34781267, DOI: 10.6004/jnccn.2021.0054.Peer-Reviewed Original ResearchConceptsB-cell lymphomaNCCN guidelinesAnti-CD19 CAR T-cell therapyB-cell non-Hodgkin lymphomaCAR T-cell therapyB-cell receptor pathwayLarge B-cell lymphomaNCCN Guidelines InsightsRelapsed/refractoryT-cell therapyNon-Hodgkin lymphomaNovel treatment optionsMantle cell lymphomaAntibody-drug conjugatesR diseaseTherapy optionsTreatment optionsCell lymphomaFollicular lymphomaSmall molecule inhibitorsLymphomaMolecular pathogenesisReceptor pathwayMolecule inhibitorsTherapyProtein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer
Mirzapoiazova T, Xiao G, Mambetsariev B, Nasser MW, Miaou E, Singhal SS, Srivastava S, Mambetsariev I, Nelson MS, Nam A, Behal A, Arvanitis LD, Atri P, Muschen M, Tissot FLH, Miser J, Kovach JS, Sattler M, Batra SK, Kulkarni P, Salgia R. Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer. Molecular Cancer Therapeutics 2021, 20: 1820-1835. PMID: 34253596, PMCID: PMC8722383, DOI: 10.1158/1535-7163.mct-21-0013.Peer-Reviewed Original ResearchConceptsProtein phosphatase 2APhosphatase 2ASerine/threonine phosphataseDNA damage responseRegulation of apoptosisSmall molecule inhibitorsGlycolytic ATP productionThreonine phosphataseTwo-dimensional cultureLB100ATP productionMolecule inhibitorsPP2AThree-dimensional spheroid modelEndothelial cell monolayersGlucose uptakeCell viabilitySCLC cellsTherapeutic targetApoptosisCell monolayersMass spectrometrySpheroid modelTumor spheroidsCellsIn silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer
Lin ZP, Al Zouabi NN, Xu ML, Bowen NE, Wu TL, Lavi ES, Huang PH, Zhu YL, Kim B, Ratner ES. In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer. Scientific Reports 2021, 11: 8042. PMID: 33850183, PMCID: PMC8044145, DOI: 10.1038/s41598-021-87325-5.Peer-Reviewed Original ResearchConceptsEpithelial ovarian cancerSmall molecule inhibitorsPARP inhibitor resistancePARP inhibitorsBRCA mutationsOvarian cancerEOC cellsPoly ADP-ribose polymerase inhibitorsMolecule inhibitorsInhibitor resistanceADP-ribose polymerase inhibitorsTumor-bearing miceNovel small molecule inhibitorPARP inhibitor olaparibDefective homologous recombination (HR) repairEOC xenograftsClinical efficacySurvival timePutative small molecule inhibitorsInhibitor olaparibPolymerase inhibitorsHR repairInhibitorsCancerHomologous recombination repairTargeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides
Dharmaratne NU, Kaplan AR, Glazer PM. Targeting the Hypoxic and Acidic Tumor Microenvironment with pH-Sensitive Peptides. Cells 2021, 10: 541. PMID: 33806273, PMCID: PMC8000199, DOI: 10.3390/cells10030541.Peer-Reviewed Original ResearchConceptsNucleic acid analoguesPH-sensitive peptideLow insertion peptideAcidic tumor microenvironmentPoor bioavailabilityInsertion peptideFluorescent dyeHigh toxicitySelective deliveryAcid analoguesSmall molecule inhibitorsNanoparticlesCancer therapeuticsMolecule inhibitorsDyePeptidesReview articleAcidityPHLIPPromising toolBioavailabilityAnaloguesDeliveryHypoxic tumor microenvironment
2020
CSIG-08. TARGETING ION TRANSPORT-REGULATORY KINASES AS A NOVEL TREATMENT FOR GLIOBLASTOMA
Schiapparelli P, Meade P, Miranda-Herrera P, Bechtle A, Issacs F, Levchenko A, Rinehart J, Quinones-Hinojosa A. CSIG-08. TARGETING ION TRANSPORT-REGULATORY KINASES AS A NOVEL TREATMENT FOR GLIOBLASTOMA. Neuro-Oncology 2020, 22: ii29-ii29. PMCID: PMC7650317, DOI: 10.1093/neuonc/noaa215.120.Peer-Reviewed Original ResearchOxidative stress-responsive kinase 1Small molecule inhibitorsGBM cellsMolecule inhibitorsAggressive primary brain tumorCell migrationComplete surgical resectionMaximal safe resectionPrimary brain tumorsAdjacent brain parenchymaCell proliferationOrthotopic murine modelPatient-derived GBM cell linesDose-dependent reductionImportant therapeutic componentGBM cell linesCell cycle analysisGBM cell migrationSurgical resectionSafe resectionBrain parenchymaCell infiltrationCell cycle arrestMurine modelRadiation therapyPotent BRD4 inhibitor suppresses cancer cell-macrophage interaction
Yin M, Guo Y, Hu R, Cai WL, Li Y, Pei S, Sun H, Peng C, Li J, Ye R, Yang Q, Wang N, Tao Y, Chen X, Yan Q. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nature Communications 2020, 11: 1833. PMID: 32286255, PMCID: PMC7156724, DOI: 10.1038/s41467-020-15290-0.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAnimalsCell CommunicationCell Cycle ProteinsCell Line, TumorCell ProliferationDisease Models, AnimalDown-RegulationDrug DesignFemaleHumansHypoxia-Inducible Factor 1, alpha SubunitMacrophage Colony-Stimulating FactorMacrophagesMice, Inbred BALB CMice, NudeNeoplasmsPhosphorylationProto-Oncogene Proteins c-mycReceptors, Granulocyte-Macrophage Colony-Stimulating FactorSignal TransductionTranscription FactorsTreatment OutcomeConceptsTumor growthMajor clinical stagesBET inhibitorsProliferation of tumorsExtraterminal domain (BET) family proteinsTumor cell proliferationClinical stageTumor shrinkageSyngeneic modelPotent BRD4 inhibitorsSmall molecule inhibitorsSolid tumorsBRD4 inhibitionTumor cellsOral bioavailabilityCancer treatmentCell proliferationBRD4 inhibitorsMolecule inhibitorsMultiple mechanismsC-MycTumorsInhibitorsPevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma
Torka P, Mavis C, Kothari S, Belliotti S, Gu J, Sundaram S, Barth M, Hernandez‐Ilizaliturri F. Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma. EJHaem 2020, 1: 122-132. PMID: 33073261, PMCID: PMC7566777, DOI: 10.1002/jha2.2.Peer-Reviewed Original ResearchActivated B cellsPre-clinical modelsSmall molecule inhibitorsClass NEDD8-activating enzyme (NAE) inhibitorEnzyme inhibitorsSCID mouse xenograft modelDiffuse large B-cell lymphomaCell linesLarge B-cell lymphomaActivity of cytarabineCytotoxic chemotherapy agentsFurther clinical studiesB-cell lymphomaViable therapeutic strategyMouse xenograft modelMolecule inhibitorsB-cell lymphoma cell linesDLBCL cell linesGCB-DLBCL cell linesLarge B-cell lymphoma cell linesAugments efficacyChemotherapy agentsClinical studiesLymphoma cell linesMonotherapy controlsStructure-Guided Identification of DNMT3B Inhibitors
Newton AS, Faver JC, Micevic G, Muthusamy V, Kudalkar SN, Bertoletti N, Anderson KS, Bosenberg MW, Jorgensen WL. Structure-Guided Identification of DNMT3B Inhibitors. ACS Medicinal Chemistry Letters 2020, 11: 971-976. PMID: 32435413, PMCID: PMC7236258, DOI: 10.1021/acsmedchemlett.0c00011.Peer-Reviewed Original ResearchUltrahigh-performance liquid chromatographyStructure-activity dataGood selectivityExploratory synthesisStructure-Guided IdentificationCrystal structureVirtual screeningAnalytical assaysActive compoundsLiquid chromatographyCompoundsSmall molecule inhibitorsPotent beingHomology modelAdditional inhibitorsAnaloguesFluorogenic assayMolecule inhibitorsSelectivitySynthesisChromatographyDockingStructureHereinIC
2018
Taming the Notch Transcriptional Regulator for Cancer Therapy
Tamagnone L, Zacchigna S, Rehman M. Taming the Notch Transcriptional Regulator for Cancer Therapy. Molecules 2018, 23: 431. PMID: 29462871, PMCID: PMC6017063, DOI: 10.3390/molecules23020431.Peer-Reviewed Original Research
2017
Parasite MIF Orthologs
Holowka T, Bucala R. Parasite MIF Orthologs. Progress In Inflammation Research 2017, 221-239. DOI: 10.1007/978-3-319-52354-5_14.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorHuman macrophage migration inhibitory factorImmune responseMIF receptor CD74Adaptive immune responsesMigration inhibitory factorPro-inflammatory activityAnimal model studiesInflammatory cytokinesReceptor CD74IL-8Novel treatmentsSmall molecule inhibitorsTherapeutic interventionsInhibitory factorInfectious diseasesMacrophage migrationHost macrophagesMIF orthologsPathogenic impactMolecule inhibitorsTautomerase activitySignal transduction pathwaysTransduction pathwaysNematode parasites
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