title: SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice.
abstract: Constitutive tyrosine kinase activity of Bcr-Abl promotes proliferation and survival of chronic myelogenous leukemia (CML) cells. Inhibition of Bcr-Abl tyrosine kinase activity or signaling proteins activated by Bcr-Abl in CML cells blocks proliferation and causes apoptotic cell death. The selective Abl kinase inhibitor, STI-571 (marketed as Gleevec), is toxic to CML cells in culture, causes regression of CML tumors in nude mice, and is currently used to treat CML patients. Here we describe a p.o. active, dual Src/Abl kinase inhibitor with potent antiproliferative activity against CML cells in culture. This 4-anilino-3-quinolinecarbonitrile (SKI-606) ablates tyrosine phosphorylation of Bcr-Abl in CML cells and of v-Abl expressed in fibroblasts. SKI-606 inhibits phosphorylation of cellular proteins, including STAT5, at concentrations that inhibit proliferation in CML cells. Phosphorylation of the autoactivation site of the Src family kinases Lyn and/or Hck is also reduced by treatment with SKI-606. Once daily oral administration of this compound at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice.
authors.affiliation: Departments of Oncology, Wyeth Research, Pearl River, New York 10965, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Golas
authors.forename: Kim
authors.initials: K
authors.lastname: Arndt
authors.forename: Carlo
authors.initials: C
authors.lastname: Etienne
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Danielle
authors.initials: D
authors.lastname: Nardin
authors.forename: James
authors.initials: J
authors.lastname: Gibbons
authors.forename: Philip
authors.initials: P
authors.lastname: Frost
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008894:Milk Proteins; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008894:Milk Proteins; D009570:Nitriles; D011804:Quinolines; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C471992:bosutinib; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases