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.
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
Substances
-
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