Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I

Stephenson, Zoe A; Harvey, Robert F; Pryde, Kenneth R; Mistry, Sarah; Hardy, Rachel E; Serreli, Riccardo; Chung, Injae; Allen, Timothy EH; Stoneley, Mark; MacFarlane, Marion; Fischer, Peter M; Hirst, Judy; Kellam, Barrie; Willis, Anne E

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.

Citation

Stephenson, Z. A., Harvey, R. F., Pryde, K. R., Mistry, S., Hardy, R. E., Serreli, R., …Willis, A. E. (2020). Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I. eLife, 9, Article e55845. https://doi.org/10.7554/elife.55845

• Journal Article Type: Article
• Acceptance Date: May 20, 2020
• Online Publication Date: May 20, 2020
• Publication Date: May 20, 2020
• Deposit Date: Jun 16, 2020
• Publicly Available Date: Jun 16, 2020
• Journal: eLife
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: e55845
• DOI: https://doi.org/10.7554/elife.55845
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Immunology and Microbiology; General Neuroscience; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4501163
• Publisher URL: https://elifesciences.org/articles/55845