Thyrosin kinase inhibitors: nilotinib

Nilotinib is an aminopyrimidine derivative that inhibits the tyrosine kinase activity of the chimeric protein BCR-ABL. The unregulated activity of the ABL tyrosine kinase in the BCR-ABL protein causes CML, and inhibition of tyrosine kinase activity is key to the treatment of the disorder. Nilotinib acts via competitive inhibition at the binding site of the BCR-ABL protein in a similar manner to imatinib, although nilotinib has a higher binding affinity and selectivity for the ABL kinase. Once bound to the ATPbinding site, nilotinib inhibits tyrosine phosphorylation of proteins involved in BCR-ABLmediated intracellular signal transduction. The inhibitory activity of nilotinib in CML cell is markedly higher than that of imatinib. In sensitive CML cell lines, the inhibitory ctivity of nilotinib is 20-50 times that of imatinib. For example, mean 50% inhibitory concentrations (IC50) of cellular BCR-ABL autophosphorylation and proliferation of Ba/F3 BCRABL cells were 21 and 25 nmol/L, respectively, for nilotinib compared with 220 and 649 nmol/L for imatinib. The inhibitory activity of nilotinib is 3- to 7- fold that of imatinib in imatinibresistant. Nilotinib demonstrated inhibitory activity in 32 of 33 imatinib-resistant CML cell lines The only BCR-ABL mutant that was not inhibited by nilotinib was T315I.