BRENDA - Enzyme Database

Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1

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.; J. Biol. Chem. 289, 13717-13725 (2014)

Data extracted from this reference:

Engineering
EC Number
Amino acid exchange
Commentary
Organism
1.1.1.42
R132H
site-directed mutagenesis
Homo sapiens
Inhibitors
EC Number
Inhibitors
Commentary
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
Commentary
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
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
1.1.1.42
isocitrate + NADP+
Homo sapiens
-
2-oxoglutarate + CO2 + NADPH + H+
-
-
r
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
1.1.1.42
Homo sapiens
P48735
-
-
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.1.1.42
isocitrate + NADP+
-
740721
Homo sapiens
2-oxoglutarate + CO2 + NADPH + H+
-
-
-
r
Temperature Optimum [C]
EC Number
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
1.1.1.42
22
-
assay at room temperature
Homo sapiens
pH Optimum
EC Number
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
1.1.1.42
7.5
-
assay at
Homo sapiens
Cofactor
EC Number
Cofactor
Commentary
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
Commentary
Organism
Inhibitor
Structure
1.1.1.42
0.000068
-
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22C
Homo sapiens
(+)-ML309
1.1.1.42
0.029
-
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22C
Homo sapiens
(-)-ML309
1.1.1.42
0.036
-
inhibition of wild-type enzyme, pH 7.5, 22C
Homo sapiens
(+)-ML309
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
1.1.1.42
NADP+
-
Homo sapiens
1.1.1.42
NADPH
-
Homo sapiens
Engineering (protein specific)
EC Number
Amino acid exchange
Commentary
Organism
1.1.1.42
R132H
site-directed mutagenesis
Homo sapiens
IC50 Value (protein specific)
EC Number
IC50 Value
IC50 Value Maximum
Commentary
Organism
Inhibitor
Structure
1.1.1.42
0.000068
-
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22C
Homo sapiens
(+)-ML309
1.1.1.42
0.029
-
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22C
Homo sapiens
(-)-ML309
1.1.1.42
0.036
-
inhibition of wild-type enzyme, pH 7.5, 22C
Homo sapiens
(+)-ML309
Inhibitors (protein specific)
EC Number
Inhibitors
Commentary
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] (protein specific)
EC Number
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
1.1.1.42
additional information
-
additional information
stopped-flow kinetics and steady-state kientics
Homo sapiens
Natural Substrates/ Products (Substrates) (protein specific)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
1.1.1.42
isocitrate + NADP+
Homo sapiens
-
2-oxoglutarate + CO2 + NADPH + H+
-
-
r
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.1.1.42
isocitrate + NADP+
-
740721
Homo sapiens
2-oxoglutarate + CO2 + NADPH + H+
-
-
-
r
Temperature Optimum [C] (protein specific)
EC Number
Temperature Optimum [C]
Temperature Optimum Maximum [C]
Commentary
Organism
1.1.1.42
22
-
assay at room temperature
Homo sapiens
pH Optimum (protein specific)
EC Number
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
1.1.1.42
7.5
-
assay at
Homo sapiens
General Information
EC Number
General Information
Commentary
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
General Information (protein specific)
EC Number
General Information
Commentary
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