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Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML

Leukemia volume 24, pages 1375–1378 (2010)Cite this article

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Three main categories of pharmacological inhibitors of kinase activity include the following: (1) type I, or ‘DFG-in’ ATP competitive inhibitors (the Asp-Phe-Gly or ‘DFG’ motif is highly conserved in protein kinases and sits near the beginning, or N terminus, of the activation loop), characterized by competition with ATP in the ATP binding site; (2) type II, or ‘DFG-out’ ATP competitive inhibitors, which bind to the ATP-binding site as well as an adjacent hydrophobic binding site accessible solely when the kinase is in an inactivated configuration and (3) non-ATP competitive inhibitors that bind at sites outside the ATP-binding site that affect kinase activity.1 Second-generation Abl inhibitors in clinical use for chronic myeloid leukemia, such as the type I inhibitor, dasatinib, and the type II inhibitor, nilotinib, show significantly more potency against BCR-ABL than imatinib, and inhibit most imatinib-resistant BCR-ABL mutants with the exception of the T315I ‘gatekeeper’ mutant.2, 3, 4, 5

HG-7-85-01 represents a new class of type II ATP-competitive inhibitors capable of inhibiting T315I-BCR-ABL, as well as gatekeeper mutants of Kit (T670I-KIT) and PDGFRα (T674I/M-PDGFRα) that are clinically observed in gastrointestinal stromal tumor and hypereosinophilic syndrome.6 HG-7-85-01 is distinctive in having the ability to accommodate either a gatekeeper threonine, present in the nonmutated forms of target kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor.

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Acknowledgements

JDG was supported by NIH Grant CA66996, and a Specialized Center of Research Award from the Leukemia and Lymphoma Society. JDG was also supported by NIH Grants CA36167 and DK50654.

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Authors and Affiliations

  1. Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA, USA

    E Weisberg, R Barrett, S Adamia, A Ray & J D Griffin

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    X Deng, H G Choi & N Gray

  3. Animal Resources Facility, Dana Farber Cancer Institute, Boston, MA, USA

    D Moreno

  4. Department of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA, USA

    A L Kung

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  1. E Weisberg
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Correspondence to E Weisberg or N Gray.

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JDG, NG and ALK have a financial interest with Novartis Pharma AG.

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Weisberg, E., Deng, X., Choi, H. et al. Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML. Leukemia 24, 1375–1378 (2010). https://doi.org/10.1038/leu.2010.107

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