6PLG

Crystal structure of human PHGDH complexed with Compound 15

Summary for 6PLG

• Entry DOI: 10.2210/pdb6plg/pdb
• Descriptor: D-3-phosphoglycerate dehydrogenase, (2S)-(4-{3-[(4,5-dichloro-1-methyl-1H-indole-2-carbonyl)amino]oxetan-3-yl}phenyl)(pyridin-3-yl)acetic acid, D-MALATE (3 entities in total)
• Functional Keywords: dehydrogenase, serine metabolism, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 273665.40

Authors

Olland, A.,Lakshminarasimhan, D.,White, A.,Suto, R.K. (deposition date: 2019-06-30, release date: 2019-07-24, Last modification date: 2024-11-06)

Primary citation

Mullarky, E.,Xu, J.,Robin, A.D.,Huggins, D.J.,Jennings, A.,Noguchi, N.,Olland, A.,Lakshminarasimhan, D.,Miller, M.,Tomita, D.,Michino, M.,Su, T.,Zhang, G.,Stamford, A.W.,Meinke, P.T.,Kargman, S.,Cantley, L.C.
Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.
Bioorg.Med.Chem.Lett., 29:2503-2510, 2019

PubMed 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 IC 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.

PubMed: 31327531
DOI: 10.1016/j.bmcl.2019.07.011

Experimental method

X-RAY DIFFRACTION (2.93 Å)