Somatic point mutations in the active site of isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple tumors. Enasidenib is a potent and selective inhibitor of the mutant IDH2. It inhibits the production of oncometabolite (R)-2-hydroxyglutarate (2HG) by the IDH2R140Q homodimer, the IDH2R140Q/WT heterodimer, and the IDH2R172K/WT heterodimer with IC50 values of 0.1, 0.03, and 0.01μM, respectively. Enasidenib also displayed time-dependent potency for inhibiting the canonical forward (oxidative) reaction in the IDH2WT homodimer with an IC50 value of 1.8μM. Moreover, Enasidenib inhibited 2HG production in HCT-116 KI (IDH2R172K, TF-1 pLVX (IDH2R140Q), TF-1 pLVX (IDH2R172K), U87MG pLVX (IDH2R172K), U87MG pLVX (IDH2R140Q) cell lines with IC50 values of 0.53, 0.02, 0.98, 1.59, and 0.01μM, respectively. In the presence of 0.1μM enasidenib, IDH2R140Q cells exhibited an approximately 50% decrease in intracellular 2HG and an increase in the percentage of cells expressing cell surface markers associated with granulocytic differentiation. Incubation of IDH2R140Q blast cells with 5μM enasidenib for 8 days significantly increased the number of cells with multilobed nuclei when compared with control cells. In tumor-bearing mice, two doses of 25 mg/kg enasidenib given 12h apart resulted in 99.2% inhibition of 2HG production in tumors. In a mouse xenograft model of primary human AML, administration of enasidenib (30 mg/kg, twice daily) for 38 days reduced serum and intracellular 2HG levels compared to vehicle-treated group[2].
作用机制
AG-221 inhibits IDH2 by allosterically stabilizing its open homodimer conformation, thereby preventing the conformational change required for catalysis[2].
Enasidenib/恩西地平 细胞实验
Cell Line
Concentration
Treated Time
Description
References
AML cells
1 µM
To evaluate the effect of Enasidenib on AML cell differentiation
Nat Med. 2018 Aug;24(8):1167-1177.
MOLM14 IDH1 R132H
2 µM
24 hours to 2 weeks
Evaluate the effect of IDH1 mutant inhibitor on 2-HG levels and mitochondrial activities, showing significant reduction in 2-HG but maintenance or increase in mitochondrial activities
J Exp Med. 2021 May 3;218(5):e20200924.
HL60 IDH1 R132H
2 µM
24 hours to 2 weeks
Evaluate the effect of IDH1 mutant inhibitor on 2-HG levels and mitochondrial activities, showing significant reduction in 2-HG but maintenance or increase in mitochondrial activities
J Exp Med. 2021 May 3;218(5):e20200924.
CDS23 cells
>100 µM (IC50)
72 hours
CDS23 cells were fully resistant to enasidenib with IC50>100 μM.
EBioMedicine. 2024 Apr;102:105090.
CDS11 cells
63.53 µM (IC50)
72 hours
CDS11 cells were partially resistant to enasidenib with IC50 of 63.53 μM.
EBioMedicine. 2024 Apr;102:105090.
L2975 cells
73.53 µM (IC50)
72 hours
L2975 cells were partially resistant to enasidenib with IC50 of 73.53 μM.
EBioMedicine. 2024 Apr;102:105090.
SW1353 cells
49.47 µM (IC50)
72 hours
SW1353 cells showed intermediate sensitivity to enasidenib with IC50 of 49.47 μM.
EBioMedicine. 2024 Apr;102:105090.
CDS17 cells
16.65-22.65 µM (IC50)
72 hours
Enasidenib significantly reduced the viability of CDS17 cells with IC50 ranging from 16.65 to 22.65 μM.
EBioMedicine. 2024 Apr;102:105090.
CB-CD34+ cells
1-25 µM
8 days
Enhanced erythroid differentiation, indicated by an increase in the percentage of CD71+GPA+ cells
J Clin Invest. 2020 Apr 1;130(4):1843-1849.
Idh2R140Q/NHD13 thymocytes
5 or 10 µM
To evaluate the effect of AG-221 on the proliferation of Idh2R140Q/NHD13 DN cells, showing a marked decrease in leukemic cell proliferation.
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