IDH2 Inhibitor

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.

Enasidenib is an oral, potent, reversible, selective inhibitor of the IDH2 mutant enzymes, with IC₅₀s of 100 and 400 nM against IDH2^R140Q and IDH2^R172K, respectively.

AGI-6780 that potently and selectively inhibits the tumor-associated mutant IDH2^R140Q with IC₅₀ of 23±1.7 nM. AGI-6780 is less potent against IDH2^WT with IC₅₀ of 190±8.1 nM.

Enasidenib mesylate is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH2 mutant enzymes.

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.

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.

CP-17 is a potent and selective IDH2/R140Q inhibitor with an IC₅₀ of 40.75 nM. CP-17 exhibits excellent selectivity of >55-fold against the wild-type IDH2. CP-17 exhibits robust D-2-HG suppression activity in TF-1 (IDH2/R140Q) cells and reverses the cellular differentiation block induced by the R140Q mutation. CP-17 can be used for acute myeloid leukemia (AML) research.

TQ05310 is an orally available inhibitor of IDH2 mutants, targeting both IDH2-R140Q (IC₅₀=136.9 nM) and IDH2-R172K (IC₅₀=37.9 nM) mutants. TQ05310 inhibits the production of 2-hydroxyglutarate (2-HG) and induces differentiation of cells expressing IDH2-R140Q and IDH2-R172K by inhibiting the enzymatic activity of mutant IDH2. TQ05310 can be used for the study of acute myeloid leukemia.

BRD2879 is a potent IDH1-R132H inhibitor with IC₅₀ values of 0.05, 2.5, >20, >20 µM for IDH1-R132H, IDH1-R132C, IDH1-WT, IDH2-R140Q, respectively. BRD2879 reduces (R)-2-hydroxyglutarate (R-2HG) levels.

Crelosidenib (gentisate) is a potent, selective and orally active mutant isocitrate dehydrogenase (IDH) inhibitor with IC₅₀ 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. Crelosidenib (gentisate) is less active at inhibiting the IDH wild-type enzymes.