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

Article Details

Citation

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

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

Leukemia. 2009 Mar;23(3):477-85. doi: 10.1038/leu.2008.334. Epub 2008 Nov 27.

PubMed ID
19039322 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
BosutinibDual specificity mitogen-activated protein kinase kinase 1ProteinHumans
Yes
Inhibitor
Details
BosutinibDual specificity mitogen-activated protein kinase kinase 2ProteinHumans
Yes
Inhibitor
Details
BosutinibSTE20-like serine/threonine-protein kinaseProteinHumans
Yes
Inhibitor
Details
BosutinibTyrosine-protein kinase HCKProteinHumans
Yes
Inhibitor
Details
BosutinibTyrosine-protein kinase TecProteinHumans
Yes
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BosutinibCalcium/calmodulin-dependent protein kinase type II subunit gammaIC 50 (nM)184N/AN/ADetails
BosutinibProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)1N/AN/ADetails
BosutinibTyrosine-protein kinase ABL1IC 50 (nM)0.5N/AN/ADetails
BosutinibTyrosine-protein kinase LynIC 50 (nM)8N/AN/ADetails