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. Epub 2016 Apr 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carbon / chemistry
  • Carbon / metabolism*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glycolysis / drug effects
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / enzymology
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Molecular Structure
  • Phosphoglycerate Dehydrogenase / antagonists & inhibitors*
  • Phosphoglycerate Dehydrogenase / metabolism
  • Purines / biosynthesis
  • Serine / biosynthesis*
  • Serine / chemistry
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Thymidine / biosynthesis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Enzyme Inhibitors
  • Purines
  • Small Molecule Libraries
  • Serine
  • Carbon
  • Phosphoglycerate Dehydrogenase
  • Thymidine
  • purine

Associated data

  • PubChem-Substance/312695986
  • PubChem-Substance/312695987
  • PubChem-Substance/312695988
  • PubChem-Substance/312695989
  • PubChem-Substance/312695990
  • PubChem-Substance/312695991
  • PubChem-Substance/312695992
  • PubChem-Substance/312695993
  • PubChem-Substance/312695994