Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

• Published in: Leukemia Vol. 23; no. 3; pp. 477 - 485
• Main Authors: Remsing Rix, L L, Rix, U, Colinge, J, Hantschel, O, Bennett, K L, Stranzl, T, Müller, A, Baumgartner, C, Valent, P, Augustin, M, Till, J H, Superti-Furga, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2009; Nature Publishing Group
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; BCR protein; Binders; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Cancer Research; Cell proliferation; Chronic myeloid leukemia; Critical Care Medicine; Dasatinib; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drug therapy; Enzyme inhibitors; Fusion Proteins, bcr-abl - antagonists & inhibitors; Gene Expression Profiling; Growth factors; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Intensive; Internal Medicine; K562 Cells - drug effects; K562 Cells - enzymology; Kinases; Leukemia; Leukemia, Myeloid, Accelerated Phase - enzymology; Leukemia, Myeloid, Accelerated Phase - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Lysates; Medical sciences; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Myeloid leukemia; Neoplasm Proteins - antagonists & inhibitors; Nerve Tissue Proteins - antagonists & inhibitors; Nitriles - chemistry; Nitriles - pharmacology; Oncology; original-article; Physiological aspects; Platelet-derived growth factor; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteomics; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Pyrimidines - pharmacology; Quinolines - chemistry; Quinolines - pharmacology; Signal Transduction - drug effects; src-Family Kinases - antagonists & inhibitors; Substrate Specificity; Thiazoles - pharmacology; Threonine; Tyrosine; United Kingdom; kinase profiling; chronic myeloid leukemia; chemical proteomics; dasatinib; bosutinib; Antineoplastic agent; Dasatinib; Targeting; Hematology; Enzyme; Tyrosine kinase inhibitor; Transferases; Chronic myelogenous leukemia; Malignant hemopathy; Bosutinib; Myeloproliferative syndrome; Kinase; Primary; Proteomics; Multikinase inhibitor; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.334

The detailed molecular mechanism of action of second-generation BCR–ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.