A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.
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.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Dana-Farber Cancer Institute, Longwood Center, Boston, Massachusetts, USA.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Michael E
0000-0003-3688-2378
ME
Pacold
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Kyle R
KR
Brimacombe
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Sze Ham
SH
Chan
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Jason M
JM
Rohde
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Caroline A
CA
Lewis
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Lotteke J Y M
LJ
Swier
New York University Langone Medical Center, New York, New York, USA.
Richard
R
Possemato
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Walter W
WW
Chen
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Lucas B
LB
Sullivan
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Brian P
BP
Fiske
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Steve
S
Cho
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Elizaveta
E
Freinkman
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, New York, USA.
Kıvanç
K
Birsoy
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Monther
M
Abu-Remaileh
Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Yoav D
YD
Shaul
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Chieh Min
CM
Liu
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Minerva
M
Zhou
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Min Jung
MJ
Koh
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Haeyoon
H
Chung
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Shawn M
SM
Davidson
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Alba
A
Luengo
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Amy Q
AQ
Wang
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Xin
X
Xu
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Adam
A
Yasgar
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Li
L
Liu
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Ganesha
G
Rai
University of Texas Southwestern Medical Center, Dallas, Texas, USA..
Kenneth D
KD
Westover
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
Matthew G
MG
Vander Heiden
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Min
M
Shen
Dana-Farber Cancer Institute, Longwood Center, Boston, Massachusetts, USA.
Nathanael S
0000-0001-5354-7403
NS
Gray
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
Matthew B
MB
Boxer
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
David M
DM
Sabatini
D000818:Animals; D002244:Carbon / Q000737:chemistry / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D050543:Phosphoglycerate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis; D012694:Serine / Q000096:biosynthesis* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D011687:Purines; D054852:Small Molecule Libraries; D012694:Serine; D002244:Carbon; D050543:Phosphoglycerate Dehydrogenase; D013936:Thymidine; C030985:purine