TY - JOUR TI - Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I AU - Stephenson, Zoe A AU - Harvey, Robert F AU - Pryde, Kenneth R AU - Mistry, Sarah AU - Hardy, Rachel E AU - Serreli, Riccardo AU - Chung, Injae AU - Allen, Timothy EH AU - Stoneley, Mark AU - MacFarlane, Marion AU - Fischer, Peter M AU - Hirst, Judy AU - Kellam, Barrie AU - Willis, Anne E A2 - Topisirovic, Ivan A2 - Cole, Philip A A2 - Topisirovic, Ivan VL - 9 PY - 2020 DA - 2020/05/20 SP - e55845 C1 - eLife 2020;9:e55845 DO - 10.7554/eLife.55845 UR - https://doi.org/10.7554/eLife.55845 AB - 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. KW - toxicophore KW - mitochondria KW - cardiac liability JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -