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

Journal Article · 06 July 2019 · Bioorganic and Medicinal Chemistry Letters

DOI: https://doi.org/10.1016/j.bmcl.2019.07.011 · OSTI ID:1569866

Mullarky, Edouard ^[1]; Xu, Jiayi  ^[2]; Robin, Anita D. ^[1]; Huggins, David J. ^[3]; Jennings, Andy ^[4]; Noguchi, Naoyoshi ^[5]; Olland, Andrea ^[6]; Lakshminarasimhan, Damodharan ^[6]; Miller, Michael ^[2]; Tomita, Daisuke ^[5]; Michino, Mayako ^[2]; Su, Taojunfeng ^[1]; Zhang, Guoan ^[1]; Stamford, Andrew W. ^[2]; Meinke, Peter T. ^[2]; Kargman, Stacia ^[2]; Cantley, Lewis C. ^[1]

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1. Weill Cornell Medical College, New York, NY (United States)
2. Tri-Institutional Therapeutics Discovery Inst., New York, NY (United States)
3. Tri-Institutional Therapeutics Discovery Inst., New York, NY (United States); Weill Cornell Medical College, New York, NY (United States)
4. Andy Jennings Consulting, LLC, San Diego, CA (United States)
5. Takeda Pharmaceutical Co., Ltd., Shonan Research Center, Fujisawa (Japan)
6. Xtal Biostructures, Natick, MA (United States)

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. In this study, 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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE; National Institutes of Health (NIH)
• Grant/Contract Number: R35CA197588
• OSTI ID: 1569866
• Journal Information: Bioorganic and Medicinal Chemistry Letters, Vol. 29, Issue 17; ISSN 0960-894X
• Publisher: ElsevierCopyright Statement
• Country of Publication: United States
• Language: ENGLISH