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Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors

Author

Listed:
  • Jianming Zhang

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA)

  • Francisco J. Adrián

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Wolfgang Jahnke

    (Novartis Institutes for Biomedical Research)

  • Sandra W. Cowan-Jacob

    (Novartis Institutes for Biomedical Research)

  • Allen G. Li

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Roxana E. Iacob

    (Northeastern University, Boston, Massachusetts 02115, USA)

  • Taebo Sim

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA
    Korea Institute of Science and Technology 39-1, Hawolgok-dong, Seongbuk-gu, Seoul, 136-791, Korea)

  • John Powers

    (Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
    Brigham and Women’s Hospital)

  • Christine Dierks

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Fangxian Sun

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Gui-Rong Guo

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Qiang Ding

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Barun Okram

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Yongmun Choi

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA)

  • Amy Wojciechowski

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA)

  • Xianming Deng

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA)

  • Guoxun Liu

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Gabriele Fendrich

    (Novartis Institutes for Biomedical Research)

  • André Strauss

    (Novartis Institutes for Biomedical Research)

  • Navratna Vajpai

    (Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland)

  • Stephan Grzesiek

    (Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland)

  • Tove Tuntland

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Yi Liu

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Badry Bursulaya

    (Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA)

  • Mohammad Azam

    (Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
    Brigham and Women’s Hospital)

  • Paul W. Manley

    (Novartis Institutes for Biomedical Research)

  • John R. Engen

    (Northeastern University, Boston, Massachusetts 02115, USA)

  • George Q. Daley

    (Harvard Medical School; Howard Hughes Medical Institute; Boston, Massachusetts 02115, USA
    Brigham and Women’s Hospital)

  • Markus Warmuth

    (Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Nathanael S. Gray

    (Dana-Farber Cancer Institute, Harvard Medical School, 250 Longwood Avenue, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA)

Abstract

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Suggested Citation

  • Jianming Zhang & Francisco J. Adrián & Wolfgang Jahnke & Sandra W. Cowan-Jacob & Allen G. Li & Roxana E. Iacob & Taebo Sim & John Powers & Christine Dierks & Fangxian Sun & Gui-Rong Guo & Qiang Ding &, 2010. "Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors," Nature, Nature, vol. 463(7280), pages 501-506, January.
    • Handle: RePEc:nat:nature:v:463:y:2010:i:7280:d:10.1038_nature08675
    DOI: 10.1038/nature08675
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    Cited by:

    1. Fanjun Li & Monifa A. Fahie & Kaitlyn M. Gilliam & Ryan Pham & Min Chen, 2022. "Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Tyler S. Beyett & Ciric To & David E. Heppner & Jaimin K. Rana & Anna M. Schmoker & Jaebong Jang & Dries J. H. Clercq & Gabriel Gomez & David A. Scott & Nathanael S. Gray & Pasi A. Jänne & Michael J. , 2022. "Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Pelin Ayaz & Agatha Lyczek & YiTing Paung & Victoria R. Mingione & Roxana E. Iacob & Parker W. Waal & John R. Engen & Markus A. Seeliger & Yibing Shan & David E. Shaw, 2023. "Structural mechanism of a drug-binding process involving a large conformational change of the protein target," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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