Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells
| Autor: | Stacia Kargman, Andrew John Jennings, Michael Miller, Andrew Stamford, Damodharan Lakshminarasimhan, Lewis C. Cantley, Anita D. Robin, Mayako Michino, David J. Huggins, Jiayi Xu, Edouard Mullarky, Andrea Olland, Daisuke Tomita, Naoyoshi Noguchi, Guoan Zhang, Peter T. Meinke, Taojunfeng Su |
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| Rok vydání: | 2019 |
| Předmět: |
Indoles
Clinical Biochemistry Pharmaceutical Science Dehydrogenase Molecular Dynamics Simulation Crystallography X-Ray 01 natural sciences Biochemistry Article Serine Structure-Activity Relationship Cell Line Tumor Drug Discovery Humans Phosphoglycerate dehydrogenase Enzyme Inhibitors Molecular Biology Phosphoglycerate Dehydrogenase Cell Proliferation chemistry.chemical_classification Indole test Binding Sites 010405 organic chemistry Organic Chemistry Oxidoreductase inhibitor Amides 0104 chemical sciences Protein Structure Tertiary 010404 medicinal & biomolecular chemistry Metabolic pathway Enzyme chemistry Molecular Medicine NAD+ kinase |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 1464-3405 |
| Popis: | 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 IC(50) 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. |
| Databáze: | OpenAIRE |
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