title: Extended kinase profile and properties of the protein kinase inhibitor nilotinib.
abstract: 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 autophosporylation and proliferation assays, well established kinase targets of nilotinib in rank order of inhibitory potency are DDR-1>DDR-2>BCR-Abl (Abl)>PDGFRalpha/beta>KIT>CSF-1R. In addition nilotinib has now been found to bind to both MAPK11 (p38beta) and MAPK12 (p38alpha), 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.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland. paul.manley@novatis.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Peter
authors.initials: P
authors.lastname: Drueckes
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fendrich
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Janis
authors.initials: J
authors.lastname: Liebetanz
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Jörg
authors.initials: J
authors.lastname: Trappe
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib