Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.
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.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T3 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
dasatinib Bosutinib bosutinib KIT platelet-derived growth factor receptor STE20 kinases ABL T315I kinase CAMK2G bosutinib SRC ABL kinase kinase BCR tyrosine and serine/threonine kinases ABL tyrosine kinase kinase SRC bosutinib ABL TEC kinases kinase bosutinib bosutinib tyrosine serine threonine bosutinib bosutinib