ap23464 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

STI571 (imatinib; Gleevec) was developed to specifically target the tyrosine kinase activity of the Bcr-Abl protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). It also inhibits the activity of c-Kit and PDGFR. It is the first-line drug for newly diagnosed CML, with remarkable efficacy to patients in the chronic phase of this cancer. However, CML patients in the accelerated phase or blast crisis often relapse due to drug resistance. STI571 fails to eradicate leukemic stem cells, and BCR-ABL(+). cells remain detectable in the majority of patients. The necessity for alternative or additional treatment for STI571-resistant leukemia resulted in the development of a second generation of drugs for targeted therapies. In this review a literature overview of the alternative inhibitors which were designed to override STI571 resistance and decrease the aberrant kinase activity of Bcr-Abl protein with higher efficiency is presented.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Benzamides; Dasatinib; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Hydroxamic Acids; Imatinib Mesylate; Indoles; Inhibitory Concentration 50; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Molecular Structure; Mutation; Panobinostat; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyridones; Pyrimidines; Thiazoles

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.

Topics: Adaptor Proteins, Signal Transducing; Adenosine Triphosphate; Amino Acids; Apoptosis; Benzamides; Cell Cycle; Cell Division; DNA-Binding Proteins; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Imatinib Mesylate; Inhibitory Concentration 50; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Milk Proteins; Models, Molecular; Mutation; Nuclear Proteins; Phosphorylation; Phosphotyrosine; Piperazines; Protein Structure, Tertiary; Pyridones; Pyrimidines; STAT5 Transcription Factor; Trans-Activators