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dc.contributor.authorHamed, Mostafa M
dc.contributor.authorDarwish, Sarah S
dc.contributor.authorHerrmann, Jennifer
dc.contributor.authorAbadi, Ashraf H
dc.contributor.authorEngel, Matthias
dc.date.accessioned2018-01-03T13:50:53Z
dc.date.available2018-01-03T13:50:53Z
dc.date.issued2017-04-13
dc.identifier.citationFirst Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents. 2017, 60 (7):2853-2868 J. Med. Chem.en
dc.identifier.issn1520-4804
dc.identifier.pmid28291344
dc.identifier.doi10.1021/acs.jmedchem.6b01774
dc.identifier.urihttp://hdl.handle.net/10033/621222
dc.description.abstractThe activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC50 for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshAntineoplastic Agentsen
dc.subject.meshBreasten
dc.subject.meshBreast Neoplasmsen
dc.subject.meshCell Line, Tumoren
dc.subject.meshFemaleen
dc.subject.meshHuman Umbilical Vein Endothelial Cellsen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshMice, Nudeen
dc.subject.meshNF-kappa Ben
dc.subject.meshNeoplasmsen
dc.subject.meshQuinazolinesen
dc.subject.meshReceptor, Epidermal Growth Factoren
dc.subject.meshSignal Transductionen
dc.subject.meshThioureaen
dc.titleFirst Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents.en
dc.typeArticleen
dc.contributor.departmentHIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1,66123 Saarbrücken, Germany.en
dc.identifier.journalJournal of medicinal chemistryen
refterms.dateFOA2018-03-14T00:00:00Z
html.description.abstractThe activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC50 for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.


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