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Literature summary extracted from

  • Davis, M.I.; Gross, S.; Shen, M.; Straley, K.S.; Pragani, R.; Lea, W.A.; Popovici-Muller, J.; DeLaBarre, B.; Artin, E.; Thorne, N.; Auld, D.S.; Li, Z.; Dang, L.; Boxer, M.B.; Simeonov, A.
    Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1 (2014), J. Biol. Chem., 289, 13717-13725.
    View publication on PubMedView publication on EuropePMC

Protein Variants

EC Number Protein Variants Comment Organism
1.1.1.42 R132H site-directed mutagenesis Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.1.1.42 (+)-ML309 reversible binding analysis and mechanism, detailed overview. The reversible inhibitor binds to IDH1 R132H competitively with respect to 2-oxoglutarate and uncompetitively with respect to NADPH. ML309 competes with 2-oxoglutarate but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-hydroxyglutarate levels. The rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active, whereas the (-) isomer is over 400fold less active for IDH1 R132H inhibition. IDH1 R132C is similarly inhibited by (-)-ML309. ML309 is also able to inhibit 2-hydroxyglutarate production in a glioblastoma cell line and had minimal cytotoxicity. In the presence of racemic ML309, 2-hydroxyglutarate levels drop rapidly Homo sapiens
1.1.1.42 (-)-ML309 reversible binding analysis and mechanism, detailed overview. The reversible inhibitor binds to IDH1 R132H competitively with respect to 2-oxoglutarate and uncompetitively with respect to NADPH. ML309 competes with 2-oxoglutarate but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-hydroxyglutarate levels. The rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active, whereas the (-) isomer is over 400fold less active for IDH1 R132H inhibition. IDH1 R132C is similarly inhibited by (-)-ML309. Wild-type IDH1 is largely unaffected by (+)-ML309. ML309 is also able to inhibit 2-hydroxyglutarate production in a glioblastoma cell line and had minimal cytotoxicity. In the presence of racemic ML309, 2-hydroxyglutarate levels drop rapidly Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.1.1.42 additional information
-
 additional information stopped-flow kinetics and steady-state kientics Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.42 isocitrate + NADP+ Homo sapiens
-
 2-oxoglutarate + CO2 + NADPH + H+
-
 r

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.42 Homo sapiens P48735
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.42 isocitrate + NADP+
-
 Homo sapiens 2-oxoglutarate + CO2 + NADPH + H+
-
 r

Synonyms

EC Number Synonyms Comment Organism
1.1.1.42 IDH1
-
 Homo sapiens
1.1.1.42 isocitrate dehydrogenase
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.1.1.42 22
-
 assay at room temperature Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.1.1.42 7.5
-
 assay at Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.42 NADP+
-
 Homo sapiens
1.1.1.42 NADPH
-
 Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
1.1.1.42 0.000068
-
 inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22°C Homo sapiens (+)-ML309
1.1.1.42 0.029
-
 inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22°C Homo sapiens (-)-ML309
1.1.1.42 0.036
-
 inhibition of wild-type enzyme, pH 7.5, 22°C Homo sapiens (+)-ML309

General Information

EC Number General Information Comment Organism
1.1.1.42 malfunction two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases Homo sapiens