2. Academic Validation
  3. Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells

Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells

  • Bioorg Med Chem Lett. 2019 Sep 1;29(17):2503-2510. doi: 10.1016/j.bmcl.2019.07.011.
Edouard Mullarky 1,  Jiayi Xu 2,  Anita D Robin 3,  David J Huggins 4,  Andy Jennings 5,  Naoyoshi Noguchi 6,  Andrea Olland 7,  Damodharan Lakshminarasimhan 7,  Michael Miller 2,  Daisuke Tomita 6,  Mayako Michino 2,  Taojunfeng Su 8,  Guoan Zhang 8,  Andrew W Stamford 2,  Peter T Meinke 2,  Stacia Kargman 2,  Lewis C Cantley 9
Affiliations

Affiliations

  • 1 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, United States; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, United States. Electronic address: edm2015@med.cornell.edu.
  • 2 Tri-Institutional Therapeutics Discovery Institute, 413 East 69th Street, New York, NY 10021, United States.
  • 3 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, United States; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, United States.
  • 4 Tri-Institutional Therapeutics Discovery Institute, 413 East 69th Street, New York, NY 10021, United States; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, United States.
  • 5 Andy Jennings Consulting, LLC, United States.
  • 6 Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 7 Xtal Biostructures, 12 Michigan Drive, Natick, MA 01760, United States.
  • 8 Proteomics and Metabolomics Core Facility, Weill Cornell Medicine, New York, NY 10021, United States.
  • 9 Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, United States; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, United States. Electronic address: lcantley@med.cornell.edu.
PMID: 31327531 DOI: 10.1016/j.bmcl.2019.07.011
Abstract

Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD+ pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of Cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.

Keywords

3-Phosphoglycerate dehydrogenase; Cancer metabolism; Inhibitor; PHGDH; PHGDH inhibitor; Serine synthesis.

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