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Radotinib is an effective inhibitor of native and kinase domain-mutant BCR-ABL1

Leukemia volume 29, pages 1939–1942 (2015)Cite this article

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Radotinib (IY5511HCl; Supect) is an oral, high-affinity BCR-ABL1 inhibitor that bears strong structural resemblance to imatinib and especially to nilotinib (Figure 1a), and was approved in Korea for second-line CML treatment in 2012. One stated motivation for developing radotinib is to provide emerging geographic regions with a more affordable option compared to other second generation TKIs.6, 7 An interim report on the efficacy and safety of radotinib in a phase II clinical trial enrolling chronic phase CML patients with resistance or intolerance to BCR-ABL1 TKIs, mostly imatinib, was recently released (clinicaltrials.gov identifier: 01602952).7 At a minimum follow-up of 12 months and a median duration of follow-up of 2 years, the phase II clinical trial results suggest that radotinib is effective and well tolerated, with major and complete cytogenetic response rates comparable to nilotinib and dasatinib in similar patient populations.8, 9 Our preclinical study was performed to gain a better understanding of the mutational liabilities associated with radotinib, currently in phase III clinical trials, and to better understand the binding mode of radotinib compared with the highly similar nilotinib.

When comparing the nilotinib and radotinib IC50 values within a given cell line, radotinib was more potent than nilotinib in two cell lines, but in both cases this was within the margin of error (native: 32.5 vs 30.6 nm, and M244V: 55.6 vs 50.8 nm). At the same time, nilotinib was significantly more potent than radotinib in several single mutants, including: G250E (306.5 vs 472.7 nm), Y253H (1719.3 vs 2804.0 nm), E255V (897.2 vs 1618.7 nm), V299L (74.4 vs 106.4 nm), F317L (100.5 vs 200.1 nm) and F359C (370.0 vs 569.8 nm). In addition, nilotinib was 2–3 times more potent in three compound mutant-expressing cell lines: G250E/V299L (347.3 vs 737.5 nm), V299L/F317L (133.6 vs 362.1 nm) and V299L/F359V (380.2 vs 805.0 nm). Nilotinib was also >3 times more potent in two cell lines: E255V/V299L (4.1-fold; 1222.3 vs 4982.0 nm), and F317L/F359V (14.4-fold; 622.9 vs 8964.3 nm; Figures 2a–c; Supplementary Table S3).

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Acknowledgements

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA178397 (MD and TO). Radotinib and financial support for the subset of cell proliferation assays comparing radotinib to nilotinib and imatinib against Ba/F3 cells expressing native or single mutant BCR-ABL1 were provided by Il-Yang Pharmaceuticals Co. Ltd., Yongin, South Korea.

Author Contributions

MSZ, NAV and KCG performed the experiments, analyzed the data and prepared the display items. NAV assisted in writing the manuscript. MSZ, MWD and TO conceptualized, planned and supervised the studies and wrote the manuscript.

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  1. M S Zabriskie and N A Vellore: These authors contributed equally to this work.

Authors and Affiliations

  1. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    M S Zabriskie, N A Vellore, K C Gantz, M W Deininger & T O'Hare

  2. Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA

    M W Deininger & T O'Hare

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  1. M S Zabriskie
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Correspondence to M W Deininger or T O'Hare.

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Zabriskie, M., Vellore, N., Gantz, K. et al. Radotinib is an effective inhibitor of native and kinase domain-mutant BCR-ABL1. Leukemia 29, 1939–1942 (2015). https://doi.org/10.1038/leu.2015.42

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