title: Design, synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1.
abstract: Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC50 value of 3.5 μM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC50 values of 0.63 and 0.32 μM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC50 values of 5.6 and 9.3 μM. Structure-activity relationships have been studied and binding mode of this chemical class has been proposed.
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: A A
authors.initials: AA
authors.lastname: Gryshchenko
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: S S
authors.initials: SS
authors.lastname: Tarnavskiy
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: K V
authors.initials: KV
authors.lastname: Levchenko
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: V G
authors.initials: VG
authors.lastname: Bdzhola
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: G P
authors.initials: GP
authors.lastname: Volynets
authors.affiliation: OTAVA Ltd, 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada.
authors.forename: A G
authors.initials: AG
authors.lastname: Golub
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: T P
authors.initials: TP
authors.lastname: Ruban
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: K V
authors.initials: KV
authors.lastname: Vygranenko
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
authors.forename: L L
authors.initials: LL
authors.lastname: Lukash
authors.affiliation: Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. Electronic address: sergiy@yarmoluk.org.ua.
authors.forename: S M
authors.initials: SM
authors.lastname: Yarmoluk
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*
chemical_list: D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: 5-Amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones; Inhibitor; Kinase assay; Protein kinase FGFR1; Virtual screening