title: Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit.
abstract: Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Gazit
authors.forename: Kevin
authors.initials: K
authors.lastname: Yee
authors.forename: Andrea
authors.initials: A
authors.lastname: Uecker
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
authors.forename: Tobias
authors.initials: T
authors.lastname: Sjöblom
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Gershon
authors.initials: G
authors.lastname: Golomb
authors.forename: Shmuel
authors.initials: S
authors.lastname: Banai
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013552:Swine; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011810:Quinoxalines; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3