ASH 2025 | Targeting mitochondrial metabolism with EB2023 to overcome venetoclax resistance in acute leukemia

EB2023 is the tool compound that inhibits just the F1 subunit of ATP synthase, which is very unique, and it has pharmacologic properties that make this a very special molecule. This allows us to break up oxphos in a way that harms oxphos-dependent cancer stem cells and metastatic tumors that doesn’t affect normal cells. We’ve seen evidence that using this agent can actually enhance venetoclax-resistant cells to become venetoclax-susceptible in leukemia. It actually has activity in a variety of other tumors, melanoma, prostate cancer, lung, and breast cancer. But our primary indication in moving this forward would be in acute leukemia. Inhibition of the F1 subunit of ATP synthase is particularly important because we know for many years that the tool compound oligomycin is toxic, that inhibits the FO subunit of ATP synthase. Other inhibitors of different proteins in the electron transport chain, like inhibitors of complex I, inhibitors of complex III, can be toxic. Most recently, there was clinical development of IACS-1079. That was an interesting drug, had great preclinical work, but it led to lactic acidosis and neuropathy, and patients with AML never really got to a dose. What we can do with this inhibition of F1 is we can have an energetic stress without having a redox stress. This allows the integrated stress response while maintaining an ADP-ATP ratio, which allows the normal cells to survive.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.”