PT  - JOURNAL ARTICLE
AU  - Yu-Hsi Lin
AU  - Nikunj Satani
AU  - Naima Hammoudi
AU  - Jeffrey J. Ackroyd
AU  - Sunada Khadka
AU  - Victoria C. Yan
AU  - Dimitra K. Georgiou
AU  - Yuting Sun
AU  - Rafal Zielinski
AU  - Theresa Tran
AU  - Susana Castro Pando
AU  - Xiaobo Wang
AU  - David Maxwell
AU  - Zhenghong Peng
AU  - Federica Pisaneschi
AU  - Pijus Mandal
AU  - Paul G. Leonard
AU  - Quanyu Xu
AU  - Qi Wu
AU  - Yongying Jiang
AU  - Barbara Czako
AU  - Zhijun Kang
AU  - John M. Asara
AU  - Waldemar Priebe
AU  - William Bornmann
AU  - Joseph R. Marszalek
AU  - Ronald A. DePinho
AU  - Florian L. Muller
TI  - Eradication of <em>ENO1</em>-deleted Glioblastoma through Collateral Lethality
AID  - 10.1101/331538
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 331538
4099  - http://biorxiv.org/content/early/2018/05/25/331538.short
4100  - http://biorxiv.org/content/early/2018/05/25/331538.full
AB  - Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show that addition of pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases potency, leading to inhibition of glycolysis and killing of ENO1-deleted glioma cells in the low nM range. But the utility of POMSF in vivo is dose-limited by severe hemolytic anemia. A derivative, POMHEX, shows equipotency to POMSF without inducing hemolytic anemia. POMHEX can eradicate intracranial orthotopic ENO1-deleted tumors, despite sub-optimal pharmacokinetic properties. Taken together, our data provide in vivo proof-of-principal for collateral lethality in precision oncology and showcase POMHEX as a useful molecule for the study of glycolysis in cancer metabolism.