1. Biochemistry and Chemical Biology
  2. Cancer Biology
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Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I

  1. Zoe A Stephenson
  2. Robert F Harvey
  3. Kenneth R Pryde
  4. Sarah Mistry
  5. Rachel E Hardy
  6. Riccardo Serreli
  7. Injae Chung
  8. Timothy EH Allen
  9. Mark Stoneley
  10. Marion MacFarlane
  11. Peter M Fischer
  12. Judy Hirst  Is a corresponding author
  13. Barrie Kellam  Is a corresponding author
  14. Anne E Willis  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Nottingham, United Kingdom
  3. Medical Research Council, United Kingdom
Research Article
  • Cited 4
  • Views 1,731
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Cite this article as: eLife 2020;9:e55845 doi: 10.7554/eLife.55845

Abstract

Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Zoe A Stephenson

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Robert F Harvey

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Kenneth R Pryde

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah Mistry

    School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Rachel E Hardy

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Riccardo Serreli

    MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Injae Chung

    MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2902-4677
  8. Timothy EH Allen

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Mark Stoneley

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Marion MacFarlane

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter M Fischer

    Division of Biomolecular Science and Medicinal Chemistry, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Judy Hirst

    Mitochondrial Biology Unit, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    jh@mrc-mbu.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  13. Barrie Kellam

    School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
    For correspondence
    barrie.kellam@nottingham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0030-9908
  14. Anne E Willis

    MRC Toxicology Unit, University of Cambridge, Leicester, United Kingdom
    For correspondence
    aew80@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1470-8531

Funding

Medical Research Council (MC_UU_000 /RG94521)

  • Zoe A Stephenson
  • Robert F Harvey
  • Kenneth Pryde
  • Anne E Willis

Medical Research Council (MC_U105663141 and MC_UU_00015/2)

  • Judy Hirst

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Ivan Topisirovic, Jewish General Hospital, Canada

Publication history

  1. Received: February 7, 2020
  2. Accepted: May 20, 2020
  3. Accepted Manuscript published: May 20, 2020 (version 1)
  4. Version of Record published: June 25, 2020 (version 2)

Copyright

© 2020, Stephenson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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