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

Leukemia volume 28, pages 961–964 (2014)Cite this article

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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.3 Identification of the key structural features of nilotinib and similar TKIs is essential for understanding their interaction with P-gp. Toward this goal, molecular docking, mutational mapping and quantitative structure–activity relationship (SAR) were used to identify nilotinib’s binding site on P-gp.

Nilotinib and imatinib were also compared for their binding orientation in the substrate-binding pocket of P-gp (Supplementary Figure S4). As described in Supplementary Results, the observed affinity differences between nilotinib and imatinib for P-gp can be explained on the basis of the above docking analysis and its comparison with the known crystal structures of imatinib and nilotinib bound to BCR-ABL kinase.9, 10

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Acknowledgements

We thank Mr George Leiman for editorial assistance. This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research and National Center for Advancing Translational Sciences at the NIH.

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Authors and Affiliations

  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S Shukla, E E Chufan, K Kapoor & S V Ambudkar

  2. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John’s University, Queens, NY, USA

    S Singh & T T Talele

  3. NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, MD, USA

    A P Skoumbourdis, M B Boxer, D Y Duveau & C J Thomas

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  1. S Shukla
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Correspondence to S V Ambudkar.

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Shukla, S., Chufan, E., Singh, S. et al. Elucidation of the structural basis of interaction of the BCR-ABL kinase inhibitor, nilotinib (Tasigna) with the human ABC drug transporter P-glycoprotein. Leukemia 28, 961–964 (2014). https://doi.org/10.1038/leu.2014.21

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