Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase

Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene-transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F-1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. Cryogenic electron microscopy (cryo-EM) of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. The combination of cellular, structural, mutagenesis, and in vivo evidence defines the mechanism of action of apoptolidin family glycomacrolides and establishes a path to address oxidative phosphorylation-dependent cancers.

Automated summary

Research has identified the molecular mechanism of action of the apoptolidin family glycomacrolides on cancer cells, showing that they selectively target the F-1 subcomplex of mitochondrial ATP synthase. In vivo studies have demonstrated that ammocidin A can suppress leukemia progression with minimal toxicity, indicating a potential path for addressing oxidative phosphorylation-dependent cancers.