Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers
Contributed by Lewis C. Cantley, December 23, 2015 (sent for review November 2, 2015; reviewed by Eyal Gottlieb and Brent R. Stockwell)
Significance
Serine supports a number of anabolic processes, including protein, lipid, and nucleic acid synthesis. Cells can either import serine or synthesize it de novo. Recently, overexpression of 3-phosphoglycerate dehydrogenase (PHGDH), the gene encoding the first committed step of serine synthesis, via focal amplification and other mechanisms, has been identified in human cancers. Cancer cell lines that overexpress PHGDH are uniquely sensitive to PHGDH knockdown whereas lines that express little PHGDH are insensitive, suggesting that PHGDH may be a clinically interesting target. Here, we report the discovery of a specific small molecule inhibitor of PHGDH, which enables preclinical evaluation of PHGDH as a target in cancer and provides a tool to study the biology of de novo serine synthesis.
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.
Acknowledgments
We thank U. Oppermann, M. G. Vander Heiden, K. R. Mattaini, and M. Yuan for technical assistance and reagents. We thank J. Johnson, Y. Zheng, H. Shim, B. D. Ngo, and other L.C.C. laboratory members for helpful discussions. L.C.C. was supported by NIH Grants P01CA117969 and P01CA120964. C.A.L. was partially supported by a PanCAN-AACR Pathway to Leadership Award and a Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation (Grant DFS-09-14). G.M.D. was supported by a PanCAN-AACR Pathway to Leadership Award. S.-M.F. was supported by a Conquer Cancer Now Award from the Concern Foundation.
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Published online: February 1, 2016
Published in issue: February 16, 2016
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Acknowledgments
We thank U. Oppermann, M. G. Vander Heiden, K. R. Mattaini, and M. Yuan for technical assistance and reagents. We thank J. Johnson, Y. Zheng, H. Shim, B. D. Ngo, and other L.C.C. laboratory members for helpful discussions. L.C.C. was supported by NIH Grants P01CA117969 and P01CA120964. C.A.L. was partially supported by a PanCAN-AACR Pathway to Leadership Award and a Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation (Grant DFS-09-14). G.M.D. was supported by a PanCAN-AACR Pathway to Leadership Award. S.-M.F. was supported by a Conquer Cancer Now Award from the Concern Foundation.
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Competing Interests
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. Agios Pharmaceuticals is identifying metabolic pathways of cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival.
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Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers, Proc. Natl. Acad. Sci. U.S.A.
113 (7) 1778-1783,
https://doi.org/10.1073/pnas.1521548113
(2016).
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