Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
- University of Cambridge, United Kingdom
- University of Nottingham, United Kingdom
- Medical Research Council, United Kingdom
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.
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All data generated or analysed during this study are included in the manuscript and supporting files
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Author details
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.
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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Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
eLife 9:e55845.
https://doi.org/10.7554/eLife.55845
