title: First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents.
abstract: The 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 IC50for 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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Campus C2.3, and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University , Campus E8.1, D-66123 Saarbrücken, Germany.|Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo , Cairo 11835, Egypt.
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Hamed
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo , Cairo 11835, Egypt.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Darwish
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus E8.1, D-66123 Saarbrücken, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo , Cairo 11835, Egypt.
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University , Campus C2.3, D-66123 Saarbrücken, Germany.
authors.forename: Matthias
authors.identifier: 0000-0001-5065-8634
authors.initials: M
authors.lastname: Engel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D011799:Quinazolines; D066246:ErbB Receptors; D013890:Thiourea