期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 29, 期 17, 页码 2503-2510出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.07.011
关键词
PHGDH; 3-Phosphoglycerate dehydrogenase; Serine synthesis; Cancer metabolism; PHGDH inhibitor; Inhibitor
资金
- Sanders Innovation & Education Initiative
- National Cancer Institute of the National Institutes of Health [R35CA197588]
- Daedalus Fund For Innovation Of Weill Cornell Medicine
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.
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