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, Klvanç Birsoy, Monther Abu-Remaileh, Yoav D. Shaul, Chieh Min Liu, Minerva Zhou, Min Jung Koh, Haeyoon Chung, Shawn M. DavidsonAlba 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

Research output: Contribution to journalArticlepeer-review

345 Scopus citations


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.

Original languageAmerican English
Pages (from-to)452-458
Number of pages7
JournalNature Chemical Biology
Issue number6
StatePublished - 1 Jun 2016

Bibliographical note

Funding Information:
The Sally Gordon Fellowship of the Damon Runyon Cancer Research Foundation (DRG-112-12), a Department of Defense Breast Cancer Research Program Postdoctoral Fellowship (BC120208), and an ASTRO Resident Seed Grant (RA-2011-1) (all to M.E.P.)., by Susan G. Komen for the Cure (grant to R.L.P.), by an EMBO Long-Term Fellowship (to M.A.-R.), by the NIH (1 R03 DA034602-01A1 to D.M.S.) and by the Stewart Trust (to D.M.S.). D.M.S. is an investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2016 Nature America, Inc.


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