An enolase inhibitor for the targeted treatment of ENO1-deleted cancers
Menée in vitro et à l'aide d'une xénogreffe de tumeur intracrânienne avec délétion au niveau du gène de l'énolase ENO1, cette étude met en évidence l'intérêt thérapeutique de POMHEX, une petite molécule inhibitrice de l'énolase
Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.
Nature Metabolism 2020