6RJ2

Crystal structure of PHGDH in complex with compound 40

6RJ2 の概要

• エントリーDOI: 10.2210/pdb6rj2/pdb
• 分子名称: D-3-phosphoglycerate dehydrogenase, SULFATE ION, ~{N}-[(1~{R})-1-[4-(ethanoylsulfamoyl)phenyl]ethyl]-2-methyl-5-phenyl-pyrazole-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: protein-ligand complex, dehydrogenase, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68210.57

構造登録者

Bader, G.,Wolkerstorfer, B.,Zoephel, A. (登録日: 2019-04-26, 公開日: 2019-08-07, 最終更新日: 2024-01-24)

主引用文献

Weinstabl, H.,Treu, M.,Rinnenthal, J.,Zahn, S.K.,Ettmayer, P.,Bader, G.,Dahmann, G.,Kessler, D.,Rumpel, K.,Mischerikow, N.,Savarese, F.,Gerstberger, T.,Mayer, M.,Zoephel, A.,Schnitzer, R.,Sommergruber, W.,Martinelli, P.,Arnhof, H.,Peric-Simov, B.,Hofbauer, K.S.,Garavel, G.,Scherbantin, Y.,Mitzner, S.,Fett, T.N.,Scholz, G.,Bruchhaus, J.,Burkard, M.,Kousek, R.,Ciftci, T.,Sharps, B.,Schrenk, A.,Harrer, C.,Haering, D.,Wolkerstorfer, B.,Zhang, X.,Lv, X.,Du, A.,Li, D.,Li, Y.,Quant, J.,Pearson, M.,McConnell, D.B.
Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) InhibitorBI-4924Disrupts Serine Biosynthesis.
J.Med.Chem., 62:7976-7997, 2019

PubMed Abstract: Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of , a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD)-competitive PHGDH inhibitor , which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD.

PubMed: 31365252
DOI: 10.1021/acs.jmedchem.9b00718

実験手法

X-RAY DIFFRACTION (2 Å)