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.

Highlights

  • The pharmaceutical industry must deliver safe and effective medicines while simultaneously limiting the costs associated with drug development, and a central part of this process is de-risking potential safety liabilities at an early stage (Morgan et al, 2018)

  • It is widely accepted that disruption of mitochondrial function is a common cause of adverse drug reactions (ADRs) and it has been proposed that mitochondrial toxicity, which has a major role in idiosyncratic drug toxicity (Uetrecht and Naisbitt, 2013), is responsible for up to 50% of post-market drug withdrawals (Will and Dykens, 2014; Dykens and Will, 2007)

  • Recent data have further shown that mubritinib, in common with known inhibitors of mitochondrial respiratory complex I (Sica et al, 2020), alters the phosphorylation status of proteins that sense changes in energy status and stimulate cellular proliferation, such as mTOR (Leibovitch and Topisirovic, 2018). In agreement with these data, we show that treatment of cells with mubritinib (Figure 1B) alters the phosphorylation status of proteins downstream of the energy sensor AMPK and impacts on mTOR signalling

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Summary

Introduction

The pharmaceutical industry must deliver safe and effective medicines while simultaneously limiting the costs associated with drug development, and a central part of this process is de-risking potential safety liabilities at an early stage (Morgan et al, 2018). Lack of mechanistic understanding about how compounds cause toxicity hampers predictions of adverse drug reactions (ADRs), and more information about the specific substructures of drug molecules that cause ADRs is required. Such information can be used to populate machine learning algorithms to generate adverse outcome pathways (AOPs) that predict likely outcomes (Dey et al, 2018) from off-target toxicities and that can be used in early phase drug design (Allen et al, 2018).

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