1. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.
- Author
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O'Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moseson EM, Rivera VM, Tang H, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Shakespeare WC, Dalgarno D, Clackson T, Sawyer TK, Deininger MW, and Druker BJ
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adenosine Triphosphate chemistry, Amino Acids genetics, Amino Acids metabolism, Apoptosis drug effects, Benzamides, Cell Cycle drug effects, Cell Division drug effects, DNA-Binding Proteins metabolism, Enzyme Inhibitors chemistry, Fusion Proteins, bcr-abl chemistry, Fusion Proteins, bcr-abl metabolism, Gene Expression Regulation, Neoplastic, HL-60 Cells, Humans, Imatinib Mesylate, Inhibitory Concentration 50, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Milk Proteins metabolism, Models, Molecular, Nuclear Proteins metabolism, Phosphorylation drug effects, Phosphotyrosine metabolism, Piperazines chemistry, Piperazines pharmacology, Protein Structure, Tertiary, Pyridones chemistry, Pyridones pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, STAT5 Transcription Factor, Trans-Activators metabolism, Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Enzyme Inhibitors pharmacology, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl genetics, Mutation genetics
- Abstract
The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5'-triphosphate (ATP)-based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl-transduced Ba/F3 cells (IC(50) = 14 nM; imatinib mesylate IC(50) = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl-expressing cells. Biochemical assays with purified glutathione S transferase (GST)-Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.
- Published
- 2004
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