You are here

Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers.

Date Posted: February 22, 2016

TitleIdentification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers.
Publication TypeJournal Article
Year of Publication2016
AuthorsMullarky E, Lucki NC, Zavareh RBeheshti, Anglin JL, Gomes AP, Nicolay BN, C Y Wong J, Christen S, Takahashi H, Singh PK, Blenis J, J Warren D, Fendt S-M, Asara JM, Denicola GM, Lyssiotis CA, Lairson LL, Cantley LC
JournalProc Natl Acad Sci U S A
Volume113
Issue7
Pagination1778-83
Date Published2016 Feb 16
ISSN1091-6490
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.

DOI10.1073/pnas.1521548113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID26831078