1. An enolase inhibitor for the targeted treatment of ENO1-deleted cancers
- Author
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Xiaobo Wang, Jeffrey J. Ackroyd, Yongying Jiang, Florian L. Muller, Yuting Sun, Federica Pisaneschi, Theresa Tran, Nikunj Satani, Cong-Dat Pham, Waldemar Priebe, Barbara Czako, Qi Wu, Paul G. Leonard, Ronald A. DePinho, Joseph R. Marszalek, John M. Asara, Pijus K. Mandal, Yasaman Barekatain, Susana Castro Pando, William G. Bornmann, Rafal Zielinski, Naima Hammoudi, Sunada Khadka, David Maxwell, Kenisha Arthur, Yu Hsi Lin, Quanyu Xu, Dimitra K. Georgiou, Victoria C. Yan, Zhijun Kang, and Zhenghong Peng
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Enolase ,Antineoplastic Agents ,Mice, SCID ,Article ,Mice ,Structure-Activity Relationship ,Glycolysis Inhibition ,In vivo ,Cell Line, Tumor ,Neoplasms ,Physiology (medical) ,Glioma ,Biomarkers, Tumor ,Internal Medicine ,medicine ,Animals ,Humans ,Glycolysis ,Enzyme Inhibitors ,Precision Medicine ,Sequence Deletion ,chemistry.chemical_classification ,business.industry ,Tumor Suppressor Proteins ,Cancer ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,DNA-Binding Proteins ,Macaca fascicularis ,Enzyme ,chemistry ,Cell culture ,Phosphopyruvate Hydratase ,Cancer research ,Female ,business - 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.
- Published
- 2020
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