An Enolase Inhibitor for the Targeted Treatment of ENO1-Deleted Cancers

Lin, Yu-Hsi; Satani, Nikunj; Hammoudi, Naima; Yan, Victoria C.; Barekatain, Yasaman; Khadka, Sunada; Ackroyd, Jeffrey J.; Georgiou, Dimitra K.; Pham, Cong-Dat; Arthur, Kenisha; Maxwell, David; Peng, Zhenghong; Leonard, Paul G.; Czako, Barbara; Pisaneschi, Federica; Mandal, Pijus; Sun, Yuting; Zielinski, Rafal; Pando, Susana Castro; Wang, Xiaobo; Tran, Theresa; Xu, Quanyu; Wu, Qi; Jiang, Yongying; Kang, Zhijun; Asara, John M.; Priebe, Waldemar; Bornmann, William; Marszalek, Joseph R.; DePinho, Ronald A.; Muller, Florian L.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We previously identified a subset of cancers harboring homozygous deletion of the glycolytic enzyme Enolase (ENO1) with 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 tumors in mice at doses well-tolerated in non-human primates. Our data provide in vivo proof-of-principal for the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential across a range of therapeutic settings.