Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase.

Abstract

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 F1 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.

• Authors: Benjamin J Reisman, Hui Guo, Haley E Ramsey, Madison T Wright, Bradley I Reinfeld, P Brent Ferrell, Gary A Sulikowski, W Kimryn Rathmell, Michael R Savona, Lars Plate, John L Rubinstein, Brian O Bachmann
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 18 Issue 4 Pg. 360-367 (04 2022) ISSN: 1552-4469 [Electronic] United States
• PMID: 34857958 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Macrolides
• Adenosine Triphosphate
• Mitochondrial Proton-Translocating ATPases
• apoptolidin

Topics

• Adenosine Triphosphate
• Humans
• Leukemia (drug therapy)
• Macrolides
• Mitochondrial Proton-Translocating ATPases (chemistry)
• Neoplasms (drug therapy)