Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1804, Issue 3, Pages 445-453Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbapap.2009.11.008
Keywords
Nilotinib; Imatinib; Abl kinase; ZAK kinase; Chronic leukaemia; Protein kinase assay
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As a drug used to treat imatinib-resistant and -intolerant, chronic and advanced phase chronic myelogenous leukaemia. nilotinib is well characterised as a potent inhibitor of the Abl tyrosine kinase activity of wild-type and imatinib-resistant mutant forms of BCR-Abl. Here we review the profile of nilotinib as a protein kinase inhibitor. Although an ATP-competitive inhibitor of Abl, nilotinib binds to a catalytically inactive conformation (DFG-out) of the activation loop. As a consequence of this, nilotinib exhibits time-dependent inhibition of Abl kinase in enzymatic assays, which can be extrapolated to other targets to explain differences between biochemical activity and cellular assays. Although these differences confound assessment of kinase selectivity, as assessed using a combination of protein binding and transphosphorylation assays, together with cellular auto phosporylation and proliferation assays, well established kinase targets of nilotinib in rank order of inhibitory potency are DDR-1>DDR-2>BCR-Abl (Abl)>PDGFR alpha/beta>KIT>CSF-1R. In addition nilotinib has now been found to bind to both MAPK11 (p38 beta) and MAPK12 (p38 alpha), as well as with very high affinity to ZAK kinase. Although neither enzymatic nor cellular data are yet available to substantiate the drug as an inhibitor of ZAK phosphorylation, modeling predicts that it binds in an ATP-competitive fashion. (C) 2009 Elsevier B.V. All rights reserved.
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