Antitumor activity of pyridoisoquinoline derivatives F91873 and F91874, novel multikinase inhibitors with activity against the anaplastic lymphoma kinase.

Abstract	The anaplastic lymphoma kinase (ALK) is a validated target for the therapy of different malignancies. Aberrant expression of constitutively active ALK chimeric proteins has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL) and has been detected in other cancers such as inflammatory myofibroblastic tumors, diffuse large B-cell lymphomas, certain non-small-cell lung cancers, rhabdomyosarcomas, neuroblastomas and glioblastomas. In the course of a screening program aimed at identifying kinase inhibitors with novel scaffolds, the two pyridoisoquinoline derivatives F91873 and F91874, were identified as multikinase inhibitors with activity against ALK in a biochemical screen. F91873 and F91874 also inhibited nucleophosmin-ALK and signal transducer and activator of transcription 3 phosphorylation in the ALCL cell line COST with the same potency. Both F91873 and F91874 behaved as ATP noncompetitive inhibitors and inhibited cell proliferation of the ALK(+) ALCL cell lines COST, PIO, and Karpas299 ALCL. This growth inhibition effect was associated with a G1-phase cell cycle arrest. Furthermore, administration of F91874 to severe combined immunodeficient mice bearing COST tumor xenografts resulted in a significant antitumor efficacy at 15 mg/kg/day, illustrating the potential utility of such compounds in the treatment of ALK-related pathologies.
Authors	Anna Kruczynski, Patrice Mayer, Arnaud Marchand, Stéphane Vispé, Emmanuel Fournier, Jean-Philippe Annereau, Viviane Brel, Jean-Marc Barret, Georges Delsol, Thierry Imbert, Jacques Fahy, Christian Bailly
Journal	Anti-cancer drugs (Anticancer Drugs) Vol. 20 Issue 5 Pg. 364-72 (Jun 2009) ISSN: 1473-5741 [Electronic] England
PMID	19322071 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents F 91873 F 91874 Protein Kinase Inhibitors Quinolizines Recombinant Fusion Proteins Thiazoles p80(NPM-ALK) protein Alk protein, mouse Anaplastic Lymphoma Kinase Protein-Tyrosine Kinases Receptor Protein-Tyrosine Kinases
Topics	Anaplastic Lymphoma Kinase Animals Antineoplastic Agents (chemical synthesis, therapeutic use) Carcinoma, Non-Small-Cell Lung (enzymology, pathology) Cell Line, Tumor (drug effects, enzymology) Female G1 Phase (drug effects) Lung Neoplasms (enzymology, pathology) Lymphoma, Large-Cell, Anaplastic (drug therapy, enzymology, pathology) Mice Mice, Inbred ICR Mice, SCID Ovarian Neoplasms (enzymology, pathology) Protein Kinase Inhibitors (chemical synthesis, therapeutic use) Protein Structure, Tertiary Protein-Tyrosine Kinases (antagonists & inhibitors) Quinolizines (chemical synthesis, therapeutic use) Receptor Protein-Tyrosine Kinases Recombinant Fusion Proteins (antagonists & inhibitors) Thiazoles (chemical synthesis, therapeutic use) Xenograft Model Antitumor Assays

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