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.
- Zoe A Stephenson
- Robert F Harvey
- Kenneth Pryde
- Anne E Willis
- Judy Hirst
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Ivan Topisirovic, Jewish General Hospital, Canada
- Received: February 7, 2020
- Accepted: May 20, 2020
- Accepted Manuscript published: May 20, 2020 (version 1)
© 2020, Stephenson et al.
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