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.

IDH2 (R172K):400 nM, IDH2 (R140Q):100nM

The compound has been demonstrated to reduce 2-HG levels by >90% and reverse histone and deoxyribonucleic acid (DNA) hypermethylation in vitro, and to induce differentiation in leukemia cell models[2].

Enasidenib is able to potently reduce 2HG found in the bone marrow, plasma and urine of engrafted mice. Treatment also induced a dose dependent, statistically significant, survival benefit. A proliferative burst of the human specific CD45+ blast cells is followed by cellular differentiation as measured by the expression of CD11b, CD14 and CD15 and cell morphology after Enasidenib treatment[2]. Enasidenib treatment also restores megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression and reverses the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells. Clinicalal trials combining IDH2 inhibitors with other targeted AML therapies are warranted in order to increase therapeutic efficacy[1].

Untranslated region-mediated luciferase reporter expression: HEK293 cells are transfected with a GEMS reporter vector that contains the luciferase open-reading frame flanked by and under post-transcriptional control of the BMI-1 5′ and 3′ UTRs. The resulting stable cells (F8) are treated with PTC-209 or vehicle control overnight, and then luciferase reporter activity is determined using Bright-Glo assays. The assays are run in triplicate for each point, and the percentage of inhibition was calculated against vehicle control.

H2O: < 1 mg/mL (insoluble or slightly soluble)

Ethanol: 100 mg/mL (211.25 mM), Sonication is recommended.

DMSO: 245 mg/mL (517.55 mM), Sonication is recommended.

10% DMSO+40% PEG300+5% Tween 80+45% Saline: 5 mg/mL (10.56 mM), Sonication is recommended.