isocitrate dehydrogenase

Isocitrate dehydrogenase (ICDH), a critical enzyme in the citric acid or tricarboxylic acid cycle, facilitates the oxidative decarboxylation of isocitrate to α-ketoglutarate while reducing NAD(P)+ to NAD(P)H, thus playing pivotal roles in cellular metabolism [1].

Ivosidenib (AG-120) is an orally available inhibitor of isocitrate dehydrogenase type 1 (IDH1) with potential antineoplastic activity. It specifically inhibits a mutated form of IDH1 in the cytoplasm, preventing the formation of the oncometabolite 2-hydroxyglutarate (2 hG), which may induce cellular differentiation and inhibit cellular proliferation in IDH1-expressing tumor cells.

BAY-1436032 is a novel, selective and orally available inhibitor of pan-mutant isocitrate dehydrogenase 1 (IDH1).

Mutant IDH1-IN-2 is an inhibitor of mutant Isocitrate dehydrogenase (IDH) proteins, with an IC50 of 16.6 nM in fluorescence biochemical assay and an IC50 of <22 nM in LS-MS biochemical assay.

Enasidenib (AG-221) is an orally available inhibitor of specific mutant forms of the mitochondrial enzyme isocitrate dehydrogenase type 2 (IDH2), with potential antineoplastic activity.

Mutant IDH1-IN-1 is a potent inhibitor of the mutant IDH1 R132 h, exhibiting an IC50 of less than 0.1 μM.

Mutant IDH1 inhibitor is an effective inhibitor of mutant IDH1 R132H (IC50: < 72 nM).

Olutasidenib (FT-2102) is under the study in the treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Olutasidenib is a highly effective, brain penetrant, and selective inhibitor of the mutant Isocitrate dehydrogenase 1 (IDH1) (IC50: 21.2 nM and 114 nM for IDH1- R132H and IDH1- R132C, respectively).

AGI-6780 is a potent and selective inhibitor of IDH2 R140Q mutant.

AGI-5198 (IDH-C35) is a potent and selective inhibitor of IDH1 R132H and R132C mutants, with IC50 values of 0.07 μM and 0.16 μM, respectively.

Vorasidenib (PVM/MA) is an inhibitor of mutant isocitrate dehydrogenase (IDH; IC50s = 31.9 and 31.7 nM for IDH1R132H and IDH2R140Q, respectively)

DS-1001b is an inhibitor of mutant IDH-1 (Isocitrate Dehydrogenase-1)

IHMT-IDH1-053 (compound 16) is an irreversible inhibitor highly selective for the IDH1 R132H mutant, with an IC50 of 4.7 nM. It preferentially targets IDH1 mutants over wild-type IDH1 and IDH2, in both their wild-type and mutant forms. In 293T cells transfected with the IDH1 R132H mutant, IHMT-IDH1-053 reduces 2-hydroxyglutarate (2-HG) production with an IC50 of 28 nM. The compound binds to the R132H protein at an allosteric site near the NADPH binding region, forming a covalent linkage with Cys269. Additionally, IHMT-IDH1-053 inhibits the growth of both the HT1080 cell line and primary acute myeloid leukemia (AML) cells harboring IDH1 R132 mutations [1].

Alternaphenol B2, a selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1m), is sourced from the coral-derived fungus Parengyodontium album SCSIO SX7W11. It exhibits inhibitory activity specifically against the IDH1 R132H mutation, with an IC50 of 41.9 μM [1].

GSK864 is an IDH1 mutant inhibitor that inhibits IDH1 mutants R132C, R132H, and R132G, and is used in the study of cardiovascular and oncology diseases.

IDH2R140Q-IN-2 is an orally active and potent IDH2R140Q inhibitor with an IC50 of 29 nM.IDH2R140Q-IN-2 possesses potential antitumour activity, reducing D2HG production in TF-1 cell lines carrying the IDH2R140Q mutation (IC50 of 10 nM) and inhibiting tumour tissue D2HG levels.IDH2R140Q-IN-2 is suitable for the study of acute myeloid leukaemia (AML).

Enasidenib mesylate (AG-221 mesylate) is a potent and selective IDH2 mutase inhibitor that promotes differentiation of leukemia myeloid cells for the treatment of acute myeloid leukemia.

AGI-026 (AGI-12026) is a novel and potent dual inhibitor of the mutant isocitrate dehydrogenase mIDH1/2 with the advantages of oral administration and penetration of the blood-brain barrier, with a drug concentration to plasma concentration ratio (brain/plasma ratio) of 1.5 in brain tissue, and the ability to reduce the accumulation of the carcinogenic metabolite d-2-hydroxyglutarate (2-HG), which is used in the study of mIDH gliomas.

Mutant IDH1-IN-4 is an mutant Isocitrate dehydrogenase 1 (IDH 1) inhibitor.

IDH-305 is an orally available, mutation-selective, and brain-penetrant IDH1 inhibitor targeting the IDH1 (R132) mutation. It is 200-fold more selective for mutant IDH1 isoforms than wild type, with IC50s of 27 nM, 28 nM, and 6.14 nM for IDH1R132H, IDH1R132C, and IDH1WT, respectively.

IDH889 is a brain penetrant, an allosteric and mutant specific IDH1 inhibitor. IDH889 has effective selectivity for IDH1 R132* mutations (IC50s: 0.02 μM, 0.072 μM, and 1.38 μM for IDH1R132H, IDH1R132C, and IDH1wt).

Ranolisib is an isocitrate dehydrogenase (IDH) inhibitor known for its antitumor activity.

Mutant IDH1-IN-3 (Compound 1) is a selective allosteric inhibitor targeting the mutant isocitrate dehydrogenase 1 (IDH1), with an IC50 of 13 nM for R132HIDH1. It effectively suppresses the production of D-2-hydroxyglutarate (2HG) in cells and is applicable for research in oncology.

Mutant IDH1-IN-7 is a highly selective inhibitor of Isocitrate Dehydrogenase 1 (IDH1) with R132H mutation (IC50 = 0.26 μM, Kd = 2.1 μM) and R132C mutation (IC50 = 1.1 μM). It does not inhibit wild-type IDH1, IDH2-wt, or IDH2R140Q. Moreover, Mutant IDH1-IN-7 reduces the production of 2-hydroxyglutarate (2-HG) in U87-MG R132H cells (EC50 = 0.55 μM) and exhibits moderate antiproliferative effects on U87-MG R132H and HT-1080 cells.