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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.
Afiliación
  • Lin YH; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Satani N; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Hammoudi N; Institute of Stroke and Cerebrovascular Disease, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • Yan VC; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Barekatain Y; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Khadka S; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ackroyd JJ; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Georgiou DK; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pham CD; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Arthur K; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Maxwell D; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Peng Z; Institutional Analytics & Informatics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Leonard PG; Cardtronics, Inc, Houston, TX, USA.
  • Czako B; Core for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pisaneschi F; Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mandal P; Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Sun Y; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Zielinski R; Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Pando SC; Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wang X; Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Tran T; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Xu Q; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wu Q; Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Jiang Y; Pharmaceutical Science Facility, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Kang Z; Pharmaceutical Science Facility, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Asara JM; Pharmaceutical Science Facility, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Priebe W; Institute for Applied Cancer Sciences, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Bornmann W; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Marszalek JR; Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • DePinho RA; Director of Drug Discovery and Development, Advanced Organic Synthesis LLC, Houston, Texas, USA.
  • Muller FL; Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Metab ; 2(12): 1413-1426, 2020 12.
Article en En | MEDLINE | ID: mdl-33230295
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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fosfopiruvato Hidratasa / Biomarcadores de Tumor / Proteínas Supresoras de Tumor / Proteínas de Unión al ADN / Inhibidores Enzimáticos / Neoplasias / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Metab Año: 2020 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fosfopiruvato Hidratasa / Biomarcadores de Tumor / Proteínas Supresoras de Tumor / Proteínas de Unión al ADN / Inhibidores Enzimáticos / Neoplasias / Antineoplásicos Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Metab Año: 2020 Tipo del documento: Article