6RJ2

Crystal structure of PHGDH in complex with compound 40

Summary for 6RJ2

• Entry DOI: 10.2210/pdb6rj2/pdb
• Descriptor: 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)
• Functional Keywords: protein-ligand complex, dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 68210.57

Authors

Bader, G.,Wolkerstorfer, B.,Zoephel, A. (deposition date: 2019-04-26, release date: 2019-08-07, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)