A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate

  • Nat Chem Biol. 2016 Jun;12(6):452-8. doi: 10.1038/nchembio.2070.
Michael E Pacold  1  2  3  4  5  6 ,  Kyle R Brimacombe  7 ,  Sze Ham Chan  1  2  3  4  6 ,  Jason M Rohde  7 ,  Caroline A Lewis  3 ,  Lotteke J Y M Swier  1  2  3  4 ,  Richard Possemato  8 ,  Walter W Chen  1  2  3  4 ,  Lucas B Sullivan  3 ,  Brian P Fiske  3 ,  Steve Cho  1  2  3  4 ,  Elizaveta Freinkman  1 ,  Kıvanç Birsoy  9 ,  Monther Abu-Remaileh  1  2  3  4 ,  Yoav D Shaul  10 ,  Chieh Min Liu  1  2  3  4 ,  Minerva Zhou  1  2  3  4 ,  Min Jung Koh  1  2  3  4 ,  Haeyoon Chung  1  2  3  4 ,  Shawn M Davidson  3 ,  Alba Luengo  3 ,  Amy Q Wang  7 ,  Xin Xu  7 ,  Adam Yasgar  7 ,  Li Liu  7 ,  Ganesha Rai  7 ,  Kenneth D Westover  11 ,  Matthew G Vander Heiden  3 ,  Min Shen  7 ,  Nathanael S Gray  5 ,  Matthew B Boxer  7 ,  David M Sabatini  1  2  3  4
Affiliations
  • 1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
  • 2. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 3. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
  • 4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 5. Dana-Farber Cancer Institute, Longwood Center, Boston, Massachusetts, USA.
  • 6. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 7. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
  • 8. New York University Langone Medical Center, New York, New York, USA.
  • 9. Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA.
  • 10. Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • 11. University of Texas Southwestern Medical Center, Dallas, Texas, USA..
PMID: 27110680 DOI: 10.1038/nchembio.2070
Abstract

Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast Cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent Cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

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