Enasidenib Chemical Properties

Melting point:

168-170°C

Boiling point:

581.0±60.0 °C(Predicted)

Density 

1.477±0.06 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to 25 mg/ml)

pka

14.70±0.29(Predicted)

form 

solid

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

InChIKey

DYLUUSLLRIQKOE-UHFFFAOYSA-N

SMILES

C(NC1=NC(C2=NC(C(F)(F)F)=CC=C2)=NC(NC2C=CN=C(C(F)(F)F)C=2)=N1)C(C)(O)C

Enasidenib Usage And Synthesis

Description

Enasidenib (1446502-11-9) is a potent (IC50’s = 100 nM IDH2R140Q homodimer, 30 nM IDH2R140Q/WT heterodimer and 10 nM IDH2R172K/WT heterodimer) and selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2).1? It suppressed the production of the oncometabolite (R)-2-Hydroxyglutarate (a competitive inhibitor of αKG-dependent dioxygenases which leads to epigenetic dysregulation) and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia cells.1,2? Recently approved for clinical use by the FDA.

Uses

Enasidenib is a first-in-class oral selective inhibitor of mutant IDH2 enzymes (isocitrate dehydrogenase 2), for the treatment of adults with relapsed or refractory IDH2-mutated acute myeloid leukemia.

Definition

ChEBI: Enasidenib is a 1,3,5-triazine which is substituted by (2-hydroxy-2-methylpropyl)nitrilo, 6-(trifluoromethyl)pyridin-2-yl and [2-(trifluoromethyl)pyridin-4-yl]nitrilo groups at positions 2,4 and 6, respectively. It is an isocitrate dehydrogenase-2 (IDH2) inhibitor which has been approved for the treatment of adults with relapsed or refractory acute myeloid leukaemia (AML). It has a role as an antineoplastic agent and an EC 1.1.1.42 (isocitrate dehydrogenase) inhibitor. It is an aminopyridine, an organofluorine compound, a secondary amino compound, a tertiary alcohol, a member of 1,3,5-triazines and an aromatic amine.

Synthesis

To a 15 L glass reactor purged with nitrogen was added 4-chloro-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoroethyl)pyridin-4-yl)-1,3,5-triazin-2-amine (1.038 kg, 2.47 mol, 1 eq.) followed by 2-methyltetrahydrofuran (6.176 kg) and N,N-diisopropylethylamine ( 0.384 kg, 2.97 mol, 1.2 eq.). The resulting mixture was stirred at room temperature and then a 2-methyltetrahydrofuran solution (2.647 kg) of 1-amino-2-methyl-2-propanol (0.265 kg, 2.97 mol, 1.2 eq.) was slowly added while maintaining the reaction temperature at 20-30 °C. After the reaction was completed, water (2.6 L) and n-heptane (2.076 kg) were added. The mixture was stirred for 20 min, the aqueous layer was separated and removed, water (2.6 L) was added again, and the pH of the aqueous phase was adjusted to 7 with 0.1 N hydrochloric acid. the aqueous layer was separated and removed, and the organic layer was washed sequentially with water (2 x 2.6 L), 4% sodium bicarbonate solution (1.1 L) and water (1.15 L). The organic layer was concentrated under vacuum to 3.4 L. 2-methyltetrahydrofuran (4.950 kg) was added and the mixture was concentrated to 3.4 L. The residue was diluted with 2-methyltetrahydrofuran (4.931 kg). The solution was clarified by passing it through a 1.2 ton in-line filter. The clarified solution was concentrated to 2.6 L. The residue was heated to 45 °C and n-heptane (2.599 kg) was added slowly while maintaining the temperature at 45 °C. The solution was then diluted with 2-methyl-1-heptane (4.931 kg). 2-Methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol (10 g) was added as a crystal seed. Again n-heptane (2.599 kg) was added slowly while maintaining 45°C. After 1 hour, the reaction mixture was cooled to 20°C. Stirring was continued at 20°C for 1 hr. The solid was collected by filtration, washed with n-heptane (2 x 1 L) and then dried under vacuum in an oven at 35 °C for 20 h. The reaction mixture was then cooled to 45 °C. The final product was obtained as 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol (1.124 kg, 96% yield) as a light yellow powder.

in vitro

ag-221 was found to be able to reduce 2-hg levels by >90%, reverse in-vitro histone and dna hypermethylation, and induce differentiation in leukemia cell model as well. in addition, a dose dependent proliferative burst of the human specific cd45+ blast cells was observed by the treatment of ag-221, as measured by the expression of cd11b, cd14, cd15 and cell morphology [1].

in vivo

the efficacy of ag-221 in a primary human aml xenograft model with the idh2 r140q mutation was studied, and the results showed that ag-221 could reduce 2-hg in the plasma, bone marrow, and urine of engrafted mice potently. in addition, the treatment of ag-221 could also induce a significant and dose dependent survival benefit as demonstrated by that all mice in the high dose treatment of ag-221 survived to the end of study [1].

IC 50

~16 nm for idh2 r140q mutant

References

[1] K. YEN. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.[J]. Cancer discovery, 2017, 7 5 1: 478-493. DOI:10.1158/2159-8290.cd-16-1034
[2] MICHAEL D AMATANGELO. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response.[J]. Blood, 2017, 130 6: 732-741. DOI:10.1182/blood-2017-04-779447

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