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Ref Type Journal Article
PMID (19039322)
Authors Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, Muller A, Baumgartner C, Valent P, Augustin M, Till JH, Superti-Furga G
Title Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.
Journal Vol Issue Date Pages Journal Short Title
Leukemia 23 3 2009 Mar 477-85 Leukemia
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Bosutinib Bosutinib 3 12
Drug Name Trade Name Synonyms Drug Classes Drug Description
Bosutinib Bosulif SKI-606|PF-5208763 ABL Inhibitor (pan) 9 AXL Inhibitor 30 BCR-ABL Inhibitor 32 BTK inhibitor 39 SRC Inhibitor 31 TNK2 Inhibitor 7 Bosulif (bosutinib) inhibits SRC and ABL kinases and has additional activity against other kinases including AXL, TNK2, and BTK, resulting in decreased pathway activation and inhibition of tumor cell proliferation (PMID: 12543790, PMID: 19039322, PMID: 26555154). Bosulif (bosutinib) is FDA-approved for use in adult and pediatric patients 1 year of age and older with Ph+ (BCR-ABL) chronic myelogenous leukemia (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References