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ASH 2025 | The mechanism of action and potential of EB2023, an OXPHOS inhibitor, in acute myeloid leukemia
Matthew Villaume, MD, PhD, Vanderbilt University Medical Center, Nashville, TN, provides insight into EB2023, an inhibitor of oxidative phosphorylation (OXPHOS) that primes mitochondria for BCL2 dependence and induces pyroptotic cell death via AMPK signaling and the unfolded protein response. Dr Villaume highlights that EB2023 targets the last step of the OXPHOS pathway, ATP synthase, leading to energetic stress without causing oxidative stress, thereby potentially improving the agent’s safety compared to other OXPHOS inhibitors. He also notes its potential synergy with venetoclax-based therapies in acute myeloid leukemia (AML), which he hopes will be investigated in future studies. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
So our molecule EB2023 is an inhibitor of OXPHOS, oxidative phosphorylation, and that builds on decades of work understanding how cancer metabolism is different from healthy tissue metabolism, with at least in leukemia and specifically leukemia stem cells seem to have an increased reliance on OXPHOS for their energy production. I think some of the most important things we learned is that not all OXPHOS inhibitors should be treated alike, and that’s especially important because previous OXPHOS inhibitors have failed in the clinic due to on-target toxicity from targeting mitochondrial metabolism...
So our molecule EB2023 is an inhibitor of OXPHOS, oxidative phosphorylation, and that builds on decades of work understanding how cancer metabolism is different from healthy tissue metabolism, with at least in leukemia and specifically leukemia stem cells seem to have an increased reliance on OXPHOS for their energy production. I think some of the most important things we learned is that not all OXPHOS inhibitors should be treated alike, and that’s especially important because previous OXPHOS inhibitors have failed in the clinic due to on-target toxicity from targeting mitochondrial metabolism. But what we found is that EB2023, by targeting the last step, ATP synthase, and specifically the F1 subunit, unlike prior ones that targeted FO, led to much less lactate production by cells. And we think effectively what it does is it causes an energetic stress, the depletion of ATP, like seen with all these OXPHOS inhibitors. But it does this without causing a redox stress. We don’t see a large rise in ROS reactive oxygen species. We don’t see depletion of the essential nutrient NAD+, nicotinamide, and we don’t see induction of reactive oxygen species. So, in general, it seems to be potentially less toxic and more safe therapy, a safe way to target this in humans, hopefully.
I think this drug, specifically, and probably a lot of inhibitors of metabolism and OXPHOS, have a lot of huge potential in AML to be combined with venetoclax-based therapies. There’s kind of a natural synergy from stressing the cell energetically and then giving them a BCL2 inhibitor. So I think the next step is early phase trials with this drug or other OXPHOS inhibitors, hopefully this drug, combined with venetoclax to treat that disease.
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