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: 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, Gina M DeNicola, Costas A Lyssiotis, Luke L Lairson, Lewis C Cantley
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 7 Pg. 1778-83 (Feb 16 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 26831078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Serine
• Phosphoglycerate Dehydrogenase

Topics

• Cell Line, Tumor
• Cell Proliferation
• Humans
• Neoplasms (metabolism, pathology)
• Phosphoglycerate Dehydrogenase (antagonists & inhibitors)
• Serine (biosynthesis)