2. Academic Validation
  3. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers

Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers

  • Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1778-83. doi: 10.1073/pnas.1521548113.
Edouard Mullarky 1,  Natasha C Lucki 2,  Reza Beheshti Zavareh 2,  Justin L Anglin 2,  Ana P Gomes 3,  Brandon N Nicolay 4,  Jenny C Y Wong 5,  Stefan Christen 6,  Hidenori Takahashi 7,  Pradeep K Singh 8,  John Blenis 3,  J David Warren 8,  Sarah-Maria Fendt 6,  John M Asara 9,  Gina M DeNicola 5,  Costas A Lyssiotis 10,  Luke L Lairson 11,  Lewis C Cantley 12
Affiliations

Affiliations

  • 1 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115;
  • 2 The California Institute for Biomedical Research, La Jolla, CA 92037;
  • 3 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065;
  • 4 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
  • 5 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
  • 6 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, Vlaams Instituut voor Biotechnologie Leuven, 3000 Leuven, Belgium;
  • 7 Department of Systems Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115;
  • 8 Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; Milstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065;
  • 9 Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115;
  • 10 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; [email protected] [email protected] [email protected].
  • 11 The California Institute for Biomedical Research, La Jolla, CA 92037; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 [email protected] [email protected] [email protected].
  • 12 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; [email protected] [email protected] [email protected].
PMID: 26831078 DOI: 10.1073/pnas.1521548113
Abstract

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the Enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and Cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in Cancer cells and was selectively toxic to Cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.

Keywords

PHGDH; cancer metabolism; inhibitor; serine.

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