title: Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers.
abstract: Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. 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 identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism.
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115;
authors.forename: Edouard
authors.initials: E
authors.lastname: Mullarky
authors.affiliation: The California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Lucki
authors.affiliation: The California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Reza
authors.initials: R
authors.lastname: Beheshti Zavareh
authors.affiliation: The California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Justin L
authors.initials: JL
authors.lastname: Anglin
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Brandon N
authors.initials: BN
authors.lastname: Nicolay
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Jenny C Y
authors.initials: JC
authors.lastname: Wong
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, Vlaams Instituut voor Biotechnologie Leuven, 3000 Leuven, Belgium;
authors.forename: Stefan
authors.initials: S
authors.lastname: Christen
authors.affiliation: Department of Systems Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115;
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; Milstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065;
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; Milstein Chemistry Core Facility, Weill Cornell Medical College, New York, NY 10065;
authors.forename: J David
authors.identifier: http://orcid.org/0000-0002-2833-2248
authors.initials: JD
authors.lastname: Warren
authors.affiliation: Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, Vlaams Instituut voor Biotechnologie Leuven, 3000 Leuven, Belgium;
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115;
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Gina M
authors.initials: GM
authors.lastname: DeNicola
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109; Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; lcantley@med.cornell.edu clyssiot@med.umich.edu llairson@scripps.edu.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: The California Institute for Biomedical Research, La Jolla, CA 92037; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037 lcantley@med.cornell.edu clyssiot@med.umich.edu llairson@scripps.edu.
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; Department of Medicine, Weill Cornell Medical College, New York, NY 10065; lcantley@med.cornell.edu clyssiot@med.umich.edu llairson@scripps.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D050543:Phosphoglycerate Dehydrogenase / Q000037:antagonists & inhibitors*; D012694:Serine / Q000096:biosynthesis*
chemical_list: D012694:Serine; D050543:Phosphoglycerate Dehydrogenase
keywords: PHGDH; cancer metabolism; inhibitor; serine
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