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

Michael E Pacold; Kyle R Brimacombe; Sze Ham Chan; Jason M Rohde; Caroline A Lewis; Lotteke J Y M Swier; Richard Possemato; Walter W Chen; Lucas B Sullivan; Brian P Fiske; Steve Cho; Elizaveta Freinkman; Kıvanç Birsoy; Monther Abu-Remaileh; Yoav D Shaul; Chieh Min Liu; Minerva Zhou; Min Jung Koh; Haeyoon Chung; Shawn M Davidson; Alba Luengo; Amy Q Wang; Xin Xu; Adam Yasgar; Li Liu; Ganesha Rai; Kenneth D Westover; Matthew G Vander Heiden; Min Shen; Nathanael S Gray; Matthew B Boxer; David M Sabatini

doi:10.1038/nchembio.2070

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.

Authors

Michael E Pacold^{1

2

3

4

5

6}, Kyle R Brimacombe⁷, Sze Ham Chan^{1

2

3

4

6}, Jason M Rohde⁷, Caroline A Lewis³, Lotteke J Y M Swier^{1

2

3

4}, Richard Possemato⁸, Walter W Chen^{1

2

3

4}, Lucas B Sullivan³, Brian P Fiske³, Steve Cho^{1

2

3

4}, Elizaveta Freinkman¹, Kıvanç Birsoy⁹, Monther Abu-Remaileh^{1

2

3

4}, Yoav D Shaul¹⁰, 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 Davidson³, Alba Luengo³, Amy Q Wang⁷, Xin Xu⁷, Adam Yasgar⁷, Li Liu⁷, Ganesha Rai⁷, Kenneth D Westover¹¹, Matthew G Vander Heiden³, Min Shen⁷, Nathanael S Gray⁵, Matthew B Boxer⁷, 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..

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding