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

  • Bioorg Med Chem. 2016 May 1;24(9):2053-9. doi: 10.1016/j.bmc.2016.03.036.
A A Gryshchenko  1 ,  S S Tarnavskiy  1 ,  K V Levchenko  1 ,  V G Bdzhola  1 ,  G P Volynets  1 ,  A G Golub  2 ,  T P Ruban  1 ,  K V Vygranenko  1 ,  L L Lukash  1 ,  S M Yarmoluk  3
Affiliations
  • 1. Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine.
  • 2. OTAVA Ltd, 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada.
  • 3. Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. Electronic address: [email protected].
PMID: 27017541 DOI: 10.1016/j.bmc.2016.03.036
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.

Keywords
5-Amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones; Inhibitor; Kinase assay; Protein kinase FGFR1; Virtual screening.
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