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Specific F1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid

Matthew T Villaume1,2,3, Haley E Ramsey1,2, Valeria Impedovo4,5

  • 1Division of Hematology and Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.

Biorxiv : the Preprint Server for Biology
|July 29, 2026
PubMed

Insights

Selective ATP synthase inhibition with EB2023 targets acute myeloid leukemia (AML) cells by creating energetic stress. This approach spares normal cells and enhances BCL2 inhibitor synergy, offering a promising therapeutic strategy for AML.

Area of Science:

  • Biochemistry
  • Oncology
  • Pharmacology

Background:

  • Acute myeloid leukemia (AML) relies heavily on oxidative phosphorylation (OXPHOS).
  • Targeting OXPHOS is a potential therapeutic strategy for AML, but on-target toxicity in healthy tissues remains a challenge.
  • Previous efforts to target OXPHOS have resulted in systemic toxicity and metabolic rewiring.

Purpose of the Study:

  • To compare the cellular effects of inhibiting different parts of the electron transport chain in AML.
  • To evaluate EB2023 (ammocidin A), a selective inhibitor of the F1 subunit of ATP synthase, for AML treatment.
  • To investigate the combination therapy of EB2023 with venetoclax in AML models.

Main Methods:

  • Comprehensive comparison of distinct electron transport chain inhibition nodes in AML cells.
  • Pharmacokinetic and pharmacodynamic monitoring of EB2023 in vivo, including AMPK phosphorylation and OPA1-mediated mitochondrial remodeling.
  • Assessment of anti-AML activity of EB2023 and venetoclax combination in cell lines and patient-derived xenograft models.
  • Evaluation of toxicity in normal hematopoietic progenitors and healthy tissues.

Main Results:

  • Selective F1 ATP synthase inhibition with EB2023 induces energetic stress in AML cells without significant redox stress or NAD+/NADH imbalance.
  • OXPHOS inhibition by EB2023 is transient in vivo, leading to mitochondrial remodeling that sensitizes AML cells to BCL2 inhibitors.
  • Combination of EB2023 and venetoclax shows potent anti-AML activity in preclinical models.
  • EB2023 spares normal hematopoietic progenitors and avoids neuropathy and detrimental metabolic rewiring in healthy tissues.

Conclusions:

  • F1-selective ATP synthase inhibition is a clinically actionable strategy for AML.
  • The duration of OXPHOS inhibition is a critical factor determining the therapeutic index.
  • EB2023 in combination with venetoclax represents a promising therapeutic approach for AML with a favorable safety profile.

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