4JA8

Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor

Summary for 4JA8

• Entry DOI: 10.2210/pdb4ja8/pdb
• Descriptor: Isocitrate dehydrogenase [NADP], mitochondrial, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1-[5-(cyclopropylsulfamoyl)-2-thiophen-3-yl-phenyl]-3-[3-(trifluoromethyl)phenyl]urea, ... (6 entities in total)
• Functional Keywords: protein-inhibitor complex, metabolic enzyme oncometabolite, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion: P48735
• Total number of polymer chains: 2
• Total formula weight: 96688.35

Authors

Wei, W.,Chen, L.,Wu, M.,Jiang, F.,Travins, J.,Qian, K.,DeLaBarre, B. (deposition date: 2013-02-18, release date: 2013-04-10, Last modification date: 2024-02-28)

Primary citation

Wang, F.,Travins, J.,DeLaBarre, B.,Penard-Lacronique, V.,Schalm, S.,Hansen, E.,Straley, K.,Kernytsky, A.,Liu, W.,Gliser, C.,Yang, H.,Gross, S.,Artin, E.,Saada, V.,Mylonas, E.,Quivoron, C.,Popovici-Muller, J.,Saunders, J.O.,Salituro, F.G.,Yan, S.,Murray, S.,Wei, W.,Gao, Y.,Dang, L.,Dorsch, M.,Agresta, S.,Schenkein, D.P.,Biller, S.A.,Su, S.M.,de Botton, S.,Yen, K.E.
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
Science, 340:622-626, 2013

PubMed Abstract: A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.

PubMed: 23558173
DOI: 10.1126/science.1234769

Experimental method

X-RAY DIFFRACTION (1.55 Å)