Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
Open Access
- 19 May 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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.Funding Information
- Medical Research Council (MC_UU_000 /RG94521)
- Medical Research Council (PUAG015)
- Medical Research Council (MC_U105663141)
- Medical Research Council (MC_UU_00015/2)
This publication has 44 references indexed in Scilit:
- A spectrophotometric coupled enzyme assay to measure the activity of succinate dehydrogenaseAnalytical Biochemistry, 2013
- Cardiac Metabolism and its Interactions With Contraction, Growth, and Survival of CardiomyocytesCirculation Research, 2013
- Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivityNature Biotechnology, 2011
- Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51)Lung Cancer, 2008
- Transhydrogenation Reactions Catalyzed by Mitochondrial NADH−Ubiquinone Oxidoreductase (Complex I)Biochemistry, 2007
- Tissue heterogeneity of the mammalian mitochondrial proteomeAmerican Journal of Physiology-Cell Physiology, 2007
- Novel HER2 selective tyrosine kinase inhibitor, TAK‐165, inhibits bladder, kidney and androgen‐independent prostate cancer in vitro and in vivoInternational Journal of Urology, 2006
- Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cellsJournal of Cell Science, 2005
- Anti-proliferative activity of L-651,582 correlates with calcium-mediated regulation of nucleotide metabolism at phosphoribosyl pyrophosphate synthetaseJournal of Cellular Physiology, 1990
- Properties of a clonal muscle cell line from rat heartExperimental Cell Research, 1976