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Identification of a Small Molecule Inhibitor of 3-Phosphoglycerate Dehydrogenase to Target Serine Biosynthesis in Cancers,” by Edouard Mullarky, Natasha C

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Identification of a Small Molecule Inhibitor of 3-Phosphoglycerate Dehydrogenase to Target Serine Biosynthesis in Cancers,” by Edouard Mullarky, Natasha C Correction BIOCHEMISTRY Correction for “Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers,” by Edouard Mullarky, Natasha C. Lucki, Reza Beheshti Zavareh, Justin L. Anglin, Ana P. Gomes, Brandon N. Nicolay, Jenny C. Y. Wong, Stefan Christen, Hidenori Takahashi, Pradeep K. Singh, John Blenis, J. David Warren, Sarah-Maria Fendt, John M. Asara,GinaM.DeNicola,CostasA.Lyssiotis,LukeL.Lairson,and Lewis C. Cantley, which appeared in issue 7, February 16, 2016, of Proc Natl Acad Sci USA (113:1778–1783; first published February 1, 2016; 10.1073/pnas.1521548113). The editors note that the date on which this manuscript was sent for review was originally published incorrectly as December 7, 2015. The date should instead appear as November 2, 2015. www.pnas.org/cgi/doi/10.1073/pnas.1602228113 CORRECTION www.pnas.org PNAS | March 15, 2016 | vol. 113 | no. 11 | E1585 Downloaded by guest on September 30, 2021 Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers Edouard Mullarkya,b,c, Natasha C. Luckid, Reza Beheshti Zavarehd, Justin L. Anglind, Ana P. Gomesa,e, Brandon N. Nicolayf, Jenny C. Y. Wonga,b, Stefan Christeng,h, Hidenori Takahashii,j,1, Pradeep K. Singhk,l, John Blenisa,e, J. David Warrenk,l, Sarah-Maria Fendtg,h, John M. Asaraj, Gina M. DeNicolaa,b, Costas A. Lyssiotism,n,2, Luke L. Lairsond,o,2, and Lewis C. Cantleya,b,2 aMeyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; bDepartment of Medicine, Weill Cornell Medical College, New York, NY 10065; cBiological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115; dThe California Institute for Biomedical Research, La Jolla, CA 92037; eDepartment of Pharmacology, Weill Cornell Medical College, New York, NY 10065; fMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; gLaboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; hLaboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, Vlaams Instituut voor Biotechnologie Leuven, 3000 Leuven, Belgium; iDepartment of Systems Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; jDivision of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; kDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065; lMilstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065; mDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; nDivision of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and oDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 Contributed by Lewis C. Cantley, December 23, 2015 (sent for review December 7, 2015; reviewed by Eyal Gottlieb and Brent R. Stockwell) Cancer cells reprogram their metabolism to promote growth and cancers (NSCLCs) overexpress PHGDH (15). Proliferation of proliferation. The genetic evidence pointing to the importance of the PHGDH-amplified cancer cell lines, and other lines that over- amino acid serine in tumorigenesis is striking. The gene encoding the express PHGDH without amplification, is inhibited by PHGDH enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which cata- knockdown. In contrast, lines that express little PHGDH are re- BIOCHEMISTRY lyzes the first committed step of serine biosynthesis, is overexpressed sistant to shRNA-mediated ablation of the pathway, presumably in tumors and cancer cell lines via focal amplification and nuclear because serine import suffices (13, 14). A detailed mechanistic factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. understanding of why some cancer cells are addicted to serine PHGDH-overexpressing cells are exquisitely sensitive to genetic ab- synthesis despite the availability of extracellular serine for import lation of the pathway. Here, we report the discovery of a selective remains unclear. Interestingly, in triple negative breast cancer small molecule inhibitor of PHGDH, CBR-5884, identified by (TNBC) and NSCLC, PHGDH amplification and overexpression screening a library of 800,000 drug-like compounds. CBR-5884 are associated with more aggressive disease (13–16). Thus, PHGDH inhibited de novo serine synthesis in cancer cells and was selec- tively toxic to cancer cell lines with high serine biosynthetic activity. Significance Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The Serine supports a number of anabolic processes, including pro- identification of a small molecule inhibitor of PHGDH not only en- tein, lipid, and nucleic acid synthesis. Cells can either import ables thorough preclinical evaluation of PHGDH as a target in can- serine or synthesize it de novo. Recently, overexpression of cers, but also provides a tool with which to study serine metabolism. 3-phosphoglycerate dehydrogenase (PHGDH), the gene encod- ing the first committed step of serine synthesis, via focal am- plification and other mechanisms, has been identified in human PHGDH | inhibitor | serine | cancer metabolism cancers. Cancer cell lines that overexpress PHGDH are uniquely sensitive to PHGDH knockdown whereas lines that express little Serine is required for a plethora of anabolic processes. Serine PHGDH are insensitive, suggesting that PHGDH may be a clini- is an abundant component of proteins and is required for the cally interesting target. Here, we report the discovery of a synthesis of lipids, including sphingolipids and phosphatidylserine, specific small molecule inhibitor of PHGDH, which enables pre- a major component of cellular membranes (1–3). Alternatively, clinical evaluation of PHGDH as a target in cancer and provides a serine hydroxymethyltransferases (SHMTs) convert serine to gly- tool to study the biology of de novo serine synthesis. cine, concomitantly charging the folate pool with “one-carbon” units (4, 5). Both glycine and folate one-carbon units are used to Author contributions: E.M., N.C.L., L.L.L., and L.C.C. designed research; E.M., N.C.L., R.B.Z., make nucleotides. Thus, serine serves numerous critically impor- J.L.A., A.P.G., B.N.N., J.C.Y.W., S.C., H.T., P.K.S., J.D.W., S.-M.F., J.M.A., G.M.D., and C.A.L. tant roles in cellular metabolism. performed research; E.M., N.C.L., R.B.Z., J.L.A., A.P.G., B.N.N., S.C., H.T., P.K.S., J.B., J.D.W., At the cellular level, serine can be imported from the extra- S.-M.F., J.M.A., G.M.D., C.A.L., L.L.L., and L.C.C. analyzed data; and E.M., C.A.L., L.L.L., cellular space via amino acid transporters (6, 7). Alternatively, and L.C.C. wrote the paper. serine can be synthesized from glucose via the phosphoserine Reviewers: E.G., Beatson Institute for Cancer Research; and B.R.S., Columbia/Howard Hughes Medical Institute. pathway (8). De novo synthesis proceeds from the glycolytic intermediate 3-phosphoglycerate (3-PG) via three sequential en- Conflict of interest statement: L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. zymatic reactions (Fig. 1A), the first of which is catalyzed by + Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing the NAD -dependent enzyme 3-phosphoglycerate dehydrogenase drugs to inhibit such enzymes to disrupt tumor cell growth and survival. (PHGDH) (9). For decades, it has been known that cancer cells 1Present address: Frontier Research Laboratories, Daiichi Sankyo Co., Shinagawa-ku, Tokyo have enhanced serine synthesis, which contributes to nucleotide 140-8710, Japan. synthesis (10, 11). Recently, focal amplifications of the gene encoding 2To whom correspondence may be addressed. Email: [email protected], clyssiot@ PHGDH have been reported, particularly in breast cancers and med.umich.edu, or [email protected]. melanomas (12–14). Additionally, KEAP1 and nuclear factor This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. erythroid-2-related factor 2 (NRF2) mutant non-small cell lung 1073/pnas.1521548113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1521548113 PNAS Early Edition | 1of6 Glucose Fig. 1. A B Screening Assay Screening for inhibitors of PHGDH. (A)Serine The Phosphoserine Pathway synthesis from glucose via the phosphoserine pathway: PHGDH PSAT1 Phosphoglycerate dehydrogenase (PHGDH) oxidizes 3PG p-Pyr p-Ser the glycolytic intermediate 3-phosphoglycerate (3-PG) to PHGDH PSAT1 PSPH + NADH Glu αKG 3PG P-Pyr P-Ser Ser NAD 3-phosphohydroxypyruvate (p-Pyr) using NAD+; phos- NAD+ NADH Glu αKG Diaphorase Resazurin phoserine amino transferase (PSAT1) transaminates p-Pyr to phosphoserine (p-Ser) using glutamate as a ni- (Ex550/Em585) trogen donor; phosphoserine phosphatase (PSPH) de- Pyruvate Primary Screen phosphorylates p-Ser to yield serine. (B) In vitro PHGDH 800K compounds C D assay. Diaphorase couples the NADH produced upon PHGDH turnover to the reduction of resazurin to fluo- 3,906 Hits rescent resorufin. Resorufin fluorescence is a proxy for (Z score < -3) PHGDH activity. PSAT1 is included to prevent product feedback inhibition of PHGDH by p-Pyr. (C) Z-score plot Z-score Diaphorase for the 800,000-compound library screened using the (triplicate) counter screen above PHGDH assay. Each point represents a single compound. A negative score indicates inhibition. (D) Screen triaging strategy. Setting a Z-score threshold − Compounds of 3 gave 3,906 putative hits. After counter-screening Hits: 408 against diaphorase to rule out false positives and con- E CBR-5884 CBR-5807 CBR-6936 CBR-9480 firming activity against PHGDH, 408 compounds re- O O H S mained. Selected compounds were profiled against a N S S S N + O S N O N S O H panel of metabolic NAD(P) dehydrogenases to ascer- O O N SH (dehydrogenase panel) S S H HN tain selectivity for PHGDH.
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