2. Academic Validation
  3. Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase

Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase

  • Nat Chem Biol. 2022 Apr;18(4):360-367. doi: 10.1038/s41589-021-00900-9.
Benjamin J Reisman 1 2,  Hui Guo 3 4,  Haley E Ramsey 5,  Madison T Wright 1,  Bradley I Reinfeld 2 6,  P Brent Ferrell 5 6,  Gary A Sulikowski 1 7,  W Kimryn Rathmell 5 6,  Michael R Savona 5 6,  Lars Plate 1 7 8,  John L Rubinstein 3 4 9,  Brian O Bachmann 10 11
Affiliations

Affiliations

  • 1 Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
  • 2 Medical Scientist Training Program, Vanderbilt University, Nashville, TN, USA.
  • 3 Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 5 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 6 Cancer Biology Program, Vanderbilt University, Nashville, TN, USA.
  • 7 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA.
  • 8 Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
  • 9 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  • 10 Department of Chemistry, Vanderbilt University, Nashville, TN, USA. [email protected].
  • 11 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA. [email protected].
PMID: 34857958 DOI: 10.1038/s41589-021-00900-9
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.

Figures
Products