IDH1 Inhibitor

Ivosidenib (AG-120) is an orally active inhibitor of isocitrate dehydrogenase 1 mutant (mIDH1) enzyme, it exhibits profound d-2-hydroxyglutatrate (2-HG) lowering in vivo. Ivosidenib (AG-120) has the potential for AML therapy due to its acceptable safety profile and clinical activity.

Vorasidenib (AG-881) is an orally available, brain penetrant second-generation dual mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) inhibitor. Vorasidenib (AG-881) exhibits nanomolar inhibition of (D)-2-hydroxyglutarate (D-2-HG), and the IC₅₀ ranges of 0.04~22 nM against IDH1 R132C, IDH1 R132G, IDH1 R132H and IDH1 R132S and 7~14 nM against IDH2 R140Q and 130 nM against IDH2 R172K. Vorasidenib can be used for the study of grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1/2 mutation.

AGI-5198 (IDH-C35) is a potent and selective mutant IDH1^R132H inhibitor with an IC₅₀ of 0.07 μM.

GSK864, a chemical probe, is an isocitrate dehydrogenase 1 (IDH1) mutant inhibitor; inhibits IDH1 mutants R132C, R132H, and R132G with IC₅₀ values of 8.8, 15.2 and 16.6 nM.

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

BAY-1436032 is a novel pan-mutant isocitrate dehydrogenase 1 (IDH1) inhibitor.

IDH-305 is an orally available, mutant-selective and brain-penetrant IDH1 inhibitor that targets IDH1 (R132) mutation. IDH-305 exhibits greater than 200 fold selectivity for mutant IDH1 isoforms vs. WT (IC₅₀= 27 nM (IDH1^R132H), 28 nM (IDH1^R132C), 6.14 µM (IDH1^WT)).

IDH1 Inhibitor 2 (compound 13) is a potent wild-type IDH1 inhibitor that exerts its activity through covalent modification of His315 with an IC₅₀ value of 110 nM. IDH1 Inhibitor 2 can dose-dependently reduce the intracellular reduced glutamine metabolic flux, thereby affecting cellular metabolic homeostasis. IDH1 Inhibitor 2 can be used to study the role of IDH1 in cellular metabolic regulation and cancer development.

DIM-C-pPhCO2Me is a nuclear receptor 4A1 (NR4A1) antagonist. DIM-C-pPhCO2Me induces Apoptosis. DIM-C-pPhCO2Me decreases PAX3-FOXO1A, N-Myc, Rassf4, MyoD1, Grem1, and DAPK1 proteins. DIM-C-pPhCO2Me decreases expression of TXNDC5 and IDH1, induces markers of ER stress (CHOP, ATF4 and p-PERK). DIM-C-pPhCO2Me inhibits renal cell carcinoma, breast cancer. DIM-C-pPhCO2Me can also be used in rhabdomyosarcoma research.

Safusidenib (AB-291; DS-1001) is an orally bioavailable, selective mutant IDH1 inhibitor. Safusidenib strongly inhibits mutant IDH1 but not wild-type IDH1. Safusidenib impairs tumor activity in chondrosarcoma. Safusidenib exhibits activity against IDH1R132H, and IDH1R132C with IC₅₀s of 15, and 130 nM in assays without any preincubation, respectively.

(R,R)-GSK321 is a wild-type isocitrate dehydrogenase 1 (WT IDH1) inhibitor with an IC₅₀ value of 120 nM. (R,R)-GSK321 as a mutant R132H IDH1 inhibitor, is an isomer of GSK321 with some wild-type cross reactivity.

Mutant IDH1-IN-1 (Agios 135) is a selective mutant IDH1 inhibitor with activity against both IDH1^R132H and IDH1^R132C. Mutant IDH1-IN-1 reduces the level of 2-hydroxyglutarate (2-HG), stabilizes mutant IDH1 protein, and restores blocked monocyte differentiation. Mutant IDH1-IN-1 can be used in tumor-related research.

Mutant IDH1-IN-2 is a inhibitor of mutant Isocitrate dehydrogenase (IDH) proteins, with IC50 of in LS-MS biochemical assay, IC50 of 16.6 nM in Fluorescence biochemical assay.

Mutant IDH1-IN-6 is a potent, selective and orally active mutant isocitrate dehydrogenase (IDH) inhibitor with IC₅₀s of 6.27 nM, 3.71 nM, 36.9 nM and 11.5 nM for IDH1 R132H, IDH1 R132C, IDH2 R140Q and IDH2 R172K mutant enzymes, respectively. Mutant IDH1-IN-6 is less active at inhibiting the IDH wild-type enzymes.

IDH1 Inhibitor 7 (Compound 88) is an IDH1 inhibitor with an IC₅₀ of less than 100 nM.

TC-E 5008 is a potent mutant IDH1 inhibitor with K_i values of 190 nM and 120 nM for R132H and R132C IDH1 mutants, respectively. TC-E 5008 exhibits very weak activity against WT-IDH1 with a K_i value of 12.3 μM. TC-E 5008 has anti-proliferative activity on multiple ER positive breast cancer cell lines.

Mutant IDH1/NAMPT-IN-1 (Compound 23h) is a dual inhibitor of mutant isocitrate dehydrogenase 1 (mutant IDH1) (IC₅₀=14.93 nM) and nicotinamide phosphoribosyltransferase (NAMPT) (IC₅₀=12.56 nM). Mutant IDH1/NAMPT-IN-1 can induce apoptosis. Mutant IDH1/NAMPT-IN-1 crosses the blood-brain barrier effectively.

IHMT-IDH1-053 (compound 16) is a highly selectivity and irreversible IDH1-mutant inhibitor with an IC₅₀ of 4.7 nM for IDH1 R132H. IHMT-IDH1-053 displays high selectivity against IDH1 mutants over IDH1 wt and IDH2 wt/mutants. IHMT-IDH1-053 inhibits 2-hydroxyglutarate (2-HG) production in IDH1 R132H mutant transfected 293T cells (IC₅₀=28 nM). IHMT-IDH1-053 binds to the IDH1 R132H protein in the allosteric pocket adjacent to the NAPDH binding pocket through a covalent bond with residue Cys269. IHMT-IDH1-053 inhibits the proliferation of HT1080 cell line and primary AML cells which both bear IDH1 R132 mutants.

ML309 is a highly selective and potent inhibitor of the R132H mutant isocitrate dehydrogenase 1 (IDH1 R132H), with an IC₅₀ of 96 nM. ML309 is a competitive inhibitor of α-KG, with a K_i value of 156 nM, and its inhibitory activity against the wild-type IDH1 is greater than 35 μM. ML309 effectively reduces the production of the tumor metabolite 2-HG in U87MG cells. ML309 can be used as a chemical probe to study the role of the mutant IDH1 in cancer.

Mutant IDH1-IN-7 is a highly selective Isocitrate Dehydrogenase 1 (IDH1) R132H (IC₅₀ = 0.26 μM, K_d = 2.1 μM)/R132C (IC₅₀ = 1.1 μM) inhibitor. Mutant IDH1-IN-7 has no inhibitory effect on wild-type IDH1, IDH2-wt, and IDH2 R140Q. Mutant IDH1-IN-7 inhibits 2-Hydroxyglutarate (2-HG) production in U87-MG R132H cells (EC₅₀ = 0.55 μM). Mutant IDH1-IN-7 exhibits moderate antiproliferative effects on U87-MG R132H and HT-1080 cells.