Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I
| Autor: | Jürgen Moll, Riccardo Colombo, Enrico Pesenti, Gunhild Keller, Stefan Balabanov, Daniel Benten, Tim H. Brümmendorf, Alessio Graziano, Artur Gontarewicz, Carsten Bokemeyer, Walter Fiedler |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
G2 Phase
medicine.drug_class Immunology Fusion Proteins bcr-abl Aurora inhibitor Aurora B kinase Mitosis Antigens CD34 Apoptosis Protein Serine-Threonine Kinases Biology Philadelphia chromosome Biochemistry Piperazines Tyrosine-kinase inhibitor Mice Aurora kinase Aurora Kinases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Aurora Kinase B Humans Danusertib Phosphorylation PHA-739358 Protein Kinase Inhibitors Adaptor Proteins Signal Transducing Cell Proliferation Nuclear Proteins Drug Synergism Imatinib DNA Neoplasm Cell Biology Hematology Protein-Tyrosine Kinases medicine.disease Molecular biology Pyrimidines Drug Resistance Neoplasm Benzamides Mutation Imatinib Mesylate Cancer research Pyrazoles Mutant Proteins medicine.drug |
| Zdroj: | Blood. 111:4355-4364 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2007-09-113175 |
| Popis: | The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL–positive and –negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34+ cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated. |
| Databáze: | OpenAIRE |
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