Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

  • Bioorg Med Chem Lett. 2003 Sep 15;13(18):3031-4. doi: 10.1016/s0960-894x(03)00640-1.
Dan Berger  1 ,  Minu Dutia ,  Dennis Powell ,  Biqi Wu ,  Allan Wissner ,  Diane H Boschelli ,  M Brawner Floyd ,  Nan Zhang ,  Nancy Torres ,  Jeremy Levin ,  Xuemei Du ,  Donald Wojciechowicz ,  Carolyn Discafani ,  Constance Kohler ,  Steven C Kim ,  Larry R Feldberg ,  Karen Collins ,  Robert Mallon
Affiliations
PMID: 12941327 DOI: 10.1016/s0960-894x(03)00640-1
Abstract

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.