An enolase inhibitor for the targeted treatment of ENO1-deleted cancers
Inhibiting glycolysis is a promising strategy for cancer treatment. Previously, we identified a subset of cancers with homozygous deletion of the glycolytic enzyme enolase (ENO1) that are highly sensitive to inhibition of its redundant paralogue, ENO2, via a strategy called collateral lethality. In this study, we demonstrate that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations. Moreover, POMHEX effectively eradicates intracranial orthotopic ENO1-deleted tumors in mice at doses well-tolerated by non-human primates. Our findings provide in vivo proof of the collateral lethality approach in precision oncology and highlight the potential of POMHEX for glycolysis inhibition in various therapeutic settings.