Pacold, Michael E.Brimacombe, Kyle R.Chan, Sze HamRohde, Jason M.Lewis, Caroline A.Swier, Lotteke J.Y.M.Possemato, RichardChen, WalterSullivan, Lucas B.Fiske, Brian P.Cho, Sung WonFreinkman, ElizavetaBirsoy, KıvançAbu-Remaileh, MontherShaul, Yoav D.Liu, Chieh MinZhou, MinervaKoh, Min JungChung, HaeyoonDavidson, Shawn M.Luengo, AlbaWang, Amy Q.Xu, XinYasgar, AdamLiu, LiRai, GaneshaWestover, Kenneth D.Vander Heiden, Matthew G.Shen, MinGray, Nathanael S.Boxer, Matthew B.Sabatini, David M.2016-11-182016Pacold, M. E., K. R. Brimacombe, S. H. Chan, J. M. Rohde, C. A. Lewis, L. J. Swier, R. Possemato, et al. 2016. “A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate.” Nature chemical biology 12 (6): 452-458. doi:10.1038/nchembio.2070. http://dx.doi.org/10.1038/nchembio.2070.1552-4450http://nrs.harvard.edu/urn-3:HUL.InstRepos:29408226Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use 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 suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.en-USJournal Article2016-11-1810.1038/nchembio.2070