2. Academic Validation
  3. An enolase inhibitor for the targeted treatment of ENO1-deleted cancers

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

  • Nat Metab. 2020 Dec;2(12):1413-1426. doi: 10.1038/s42255-020-00313-3.
Yu-Hsi Lin 1,  Nikunj Satani 1 2,  Naima Hammoudi 1,  Victoria C Yan 1,  Yasaman Barekatain 1,  Sunada Khadka 1,  Jeffrey J Ackroyd 1,  Dimitra K Georgiou 1,  Cong-Dat Pham 1,  Kenisha Arthur 1,  David Maxwell 3,  Zhenghong Peng 4,  Paul G Leonard 5 6,  Barbara Czako 6,  Federica Pisaneschi 1,  Pijus Mandal 6,  Yuting Sun 6,  Rafal Zielinski 7,  Susana Castro Pando 1,  Xiaobo Wang 1,  Theresa Tran 1,  Quanyu Xu 8,  Qi Wu 8,  Yongying Jiang 8,  Zhijun Kang 6,  John M Asara 9,  Waldemar Priebe 7,  William Bornmann 10,  Joseph R Marszalek 11,  Ronald A DePinho 12,  Florian L Muller 13
Affiliations

Affiliations

  • 1 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Institute of Stroke and Cerebrovascular Disease, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 3 Institutional Analytics & Informatics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Cardtronics, Inc, Houston, TX, USA.
  • 5 Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Pharmaceutical Science Facility, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 10 Director of Drug Discovery and Development, Advanced Organic Synthesis LLC, Houston, Texas, USA.
  • 11 Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 12 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 13 Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA. aettius@aol.com.
PMID: 33230295 DOI: 10.1038/s42255-020-00313-3
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.

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