National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM092218
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA226833
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35 GM133552
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
K23 HL138291
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM065086
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
T32 GM007347
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
F30 CA236131
米国
引用
ジャーナル: Nat Chem Biol / 年: 2022 タイトル: Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase. 著者: 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 ...著者: 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 / 要旨: Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene- ...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 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.