4XRX

Crystal structure of a metabolic reductase with (E)-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one

Summary for 4XRX

• Entry DOI: 10.2210/pdb4xrx/pdb
• Related: 4XS3
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[(E)-(1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl]pyridin-2(1H)-one (3 entities in total)
• Functional Keywords: oxidoreductase/oxidoreductase inhibitor, oxidoreductase-oxidoreductase inhibitor complex
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 95128.46

Authors

Zheng, B.,Wu, F.,Jiang, H.,Kogiso, M.,Yao, Y.,Zhou, C.,Li, X.,Song, Y. (deposition date: 2015-01-21, release date: 2015-12-09, Last modification date: 2024-02-28)

Primary citation

Wu, F.,Jiang, H.,Zheng, B.,Kogiso, M.,Yao, Y.,Zhou, C.,Li, X.N.,Song, Y.
Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
J.Med.Chem., 58:6899-6908, 2015

PubMed Abstract: Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce α-ketoglutaric acid (α-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.

PubMed: 26280302
DOI: 10.1021/acs.jmedchem.5b00684

Experimental method

X-RAY DIFFRACTION (3.2 Å)