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  • An enolase inhibitor for the targeted treatment of ENO1-deleted cancers.

An enolase inhibitor for the targeted treatment of ENO1-deleted cancers.

Nature metabolism (2020-11-25)
Yu-Hsi Lin, Nikunj Satani, Naima Hammoudi, Victoria C Yan, Yasaman Barekatain, Sunada Khadka, Jeffrey J Ackroyd, Dimitra K Georgiou, Cong-Dat Pham, Kenisha Arthur, David Maxwell, Zhenghong Peng, Paul G Leonard, Barbara Czako, Federica Pisaneschi, Pijus Mandal, Yuting Sun, Rafal Zielinski, Susana Castro Pando, Xiaobo Wang, Theresa Tran, Quanyu Xu, Qi Wu, Yongying Jiang, Zhijun Kang, John M Asara, Waldemar Priebe, William Bornmann, Joseph R Marszalek, Ronald A DePinho, Florian L Muller
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Deuterium oxide, 99.9 atom % D, contains 0.05 wt. % 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid, sodium salt
Sigma-Aldrich
Deuterium oxide, 99.9 atom % D
Sigma-Aldrich
Hexarelin, ≥90% (HPLC)
Sigma-Aldrich
Anti-GAPDH antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
1,3-Propylene sulfite, 99%