6plg

Crystal structure of human PHGDH complexed with Compound 15

spinqualitylabelsall models 6plg, resolution 2.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6plg is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.93Å Ligands: MLT, ONS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SERA_HUMAN Defects in PHGDH are the cause of phosphoglycerate dehydrogenase deficiency (PHGDH deficiency) [MIM:601815. It is characterized by congenital microcephaly, psychomotor retardation, and seizures. Function SERA_HUMAN Publication Abstract from PubMed 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. Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.,Mullarky E, Xu J, Robin AD, Huggins DJ, Jennings A, Noguchi N, Olland A, Lakshminarasimhan D, Miller M, Tomita D, Michino M, Su T, Zhang G, Stamford AW, Meinke PT, Kargman S, Cantley LC Bioorg Med Chem Lett. 2019 Jul 6. pii: S0960-894X(19)30456-1. doi:, 10.1016/j.bmcl.2019.07.011. PMID:31327531 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoglycerate dehydrogenase

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