title: Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors.
abstract: Inhibition of receptor tyrosine kinases (RTKs) continued to be a successful approach for the treatment of many types of human cancers and many potent small molecules kinase inhibitors have been discovered the last decade. In the present study, we describe the synthesis of thienopyrimidine derivatives and their pharmacological evaluation against nine kinases (EGFR, PDGFR-ß, c-Kit, c-Met, Src, Raf, VEGFR-1, -2 and -3). Most of the synthesized compounds showed from moderate to potent activities against c-Kit with IC50 values in the nanomolar range. Among them, 4-anilino(urea)thienopyrimidine analogs showed selectivity and potent c-Kit inhibition with IC50 values less than 6 nM. Docking simulation was performed for the most promising compound 9 into the c-Kit active site to determine the potential binding mode. This study reveal that the 4-anilino(urea)thienopyrimidine is an interesting scaffold to design novel potent and selective c-Kit inhibitors which may make promising candidates for cancers where c-Kit receptors are overexpressed.
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Ravez
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France; Univ. Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, FED 4260, F-59000 Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Arsenlis
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Barczyk
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dupont
authors.affiliation: Université Catholique de Louvain, Medicinal Chemistry Research Group (CMFA), B1.73.10, Louvain Drug Research Institute (LDRI), B-1200 Bruxelles, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.affiliation: Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes-Equipe 3 (HECRIN), F-57070 Metz Technopôle, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hesse
authors.affiliation: Université de Lorraine, UMR CNRS 7565, Structure et Réactivité des Systèmes Moléculaires Complexes-Equipe 3 (HECRIN), F-57070 Metz Technopôle, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France; Univ. Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, FED 4260, F-59000 Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Depreux
authors.affiliation: Univ. Lille, Institut de Chimie Pharmaceutique Albert Lespagnol-ICPAL, 3, rue du Professeur Laguesse, F-59006 Lille, France; Univ. Lille, CHU Lille, EA 7365-GRITA-Groupe de Recherche sur les formes Injectables et les Technologies Associées, FED 4260, F-59000 Lille, France. Electronic address: laurence.goossens@univ-lille2.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Goossens
mesh_terms: D001665:Binding Sites; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D014508:Urea; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases
keywords: Cancer; Kinase inhibitors; Thienopyrimidine; Urea; c-Kit