Elucidation of the structural basis of interaction of the BCR-ABL kinase inhibitor, nilotinib (Tasigna) with the human ABC drug transporter P-glycoprotein

Nilotinib, imatinib (structures are shown in Supplementary Figure S1) and other tyrosine kinase inhibitors (TKIs) have been shown to be transported by the ATP-binding cassette (ABC) drug transporters P-glycoprotein (P-gp) and ABCG2.1, 2 This is clinically important as the transporters not only hamper the bioavailability of these TKIs but may also cause the emergence of drug resistance in patients. We have previously shown that imatinib and nilotinib interact at the substrate-binding pocket of ABC transporters, but do not interact at the adenosine triphosphate (ATP) sites of these transporters. Identification of the key structural features of nilotinib and similar TKIs is essential for understanding their interaction with P-gp.