@article{b83ddf5b0d474af6a2769a1af9b6f255,
title = "A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate",
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.",
author = "Pacold, {Michael E.} and Brimacombe, {Kyle R.} and Chan, {Sze Ham} and Rohde, {Jason M.} and Lewis, {Caroline A.} and Swier, {Lotteke J Y M} and Richard Possemato and Chen, {Walter W.} and Sullivan, {Lucas B.} and Fiske, {Brian P.} and Steve Cho and Elizaveta Freinkman and Klvan{\c c} Birsoy and Monther Abu-Remaileh and Shaul, {Yoav D.} and Liu, {Chieh Min} and Minerva Zhou and Koh, {Min Jung} and Haeyoon Chung and Davidson, {Shawn M.} and Alba Luengo and Wang, {Amy Q.} and Xin Xu and Adam Yasgar and Li Liu and Ganesha Rai and Westover, {Kenneth D.} and {Vander Heiden}, {Matthew G.} and Min Shen and Gray, {Nathanael S.} and Boxer, {Matthew B.} and Sabatini, {David M.}",
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.",
year = "2016",
month = jun,
day = "1",
doi = "10.1038/nchembio.2070",
language = "English (US)",
volume = "12",
pages = "452--458",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "6",
}