Nilotinib was developed using a rational design strategy based on the premise that Bcr-Abl inhibitors are more potent and selective than imatinib could be developed by making modest changes in this molecule (15). An analysis of the structure of imatinib and that of the Abl kinase domain indicated that changes to the structure's domain that binds deep into the adenosine triphosphate (ATP)-binding pocket would be likely to decrease its efficacy, but that modification of the methylpiperazinyl group of imatinib that lies along a partially hydrophobic group on the surface of Abl kinase might improve binding characteristics. Substitutions in this ring system resulted in the discovery of nilotinib, which is structurally similar to imatinib (Fig. 1) (20).
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