title: [Development and biochemical characterization of EGFR/c-Met dual inhibitors].
abstract: The epidermal growth factor receptor (EGFR) family has been well-known for more than ten years as the target of non-small lung carcinoma (NSCLC) which is one of the leading cause of mortality among the cancer types. The receptor tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib) which have been applied in the therapy, are not able to inhibit the progression of this disease perfectly because of resistance. It has been demonstrated that the amplification of mesenchymal-epithelial transition factor (c-Met) or secondary mutation of EGFR kinase causes the resistance against EGFR inhibitors in 18-20 percent of the cases. Clinical candidates inhibiting both of EGFR and c-Met kinases are unknown in the literature. We have developed quinoline-based inhibitors in our research project, which inhibit both kinases in submicromolar range in enzymatic assays, moreover we have demonstrated by western blot analysis that these compounds inhibit the autophosphorylation in vivo. The binding of the effective compounds was examined by in silico and docking simulations.
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: Bálint
authors.initials: B
authors.lastname: Szokol
authors.affiliation: Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet, Semmelweis Egyetem.
authors.forename: Pál
authors.initials: P
authors.lastname: Gyulavári
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Baska
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: Kurkó
authors.initials: K
authors.lastname: Ibolya
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Greff
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: Kis-Csaba
authors.initials: KC
authors.lastname: Szántai
authors.affiliation: Max Planck Institute of Biochemistry, Department of Molecular Biology, München.
authors.forename: Orfi
authors.initials: O
authors.lastname: Zoltán
authors.affiliation: Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet, Semmelweis Egyetem.
authors.forename: István
authors.initials: I
authors.lastname: Peták
authors.affiliation: Max Planck Institute of Biochemistry, Department of Molecular Biology, München.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Axel
authors.affiliation: Orvosi Vegytani, Molekuláris Biológiai és Patobiokémiai Intézet, Semmelweis Egyetem.
authors.forename: Tibor
authors.initials: T
authors.lastname: Vantus
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.affiliation: Vichem Chemie Kutató Kft.
authors.forename: László
authors.initials: L
authors.lastname: Orfi
mesh_terms: D000077716:Afatinib; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D002460:Cell Line; D045744:Cell Line, Tumor; D003198:Computer Simulation; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000631:Aminopyridines; D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D007093:Imidazoles; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D011728:Pyridones; D011799:Quinazolines; D011804:Quinolines; D000077341:Lapatinib; D000077716:Afatinib; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; D011494:Protein Kinases; C091973:autophosphorylation-dependent multifunctional protein kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib