Enasidenib (AG-221) counteracts the alterations induced by mutant IDH2 on DNA methylation in mutant stem/progenitor cells, fostering differentiation and inhibiting the self-renewal capabilities of IDH2-mutant leukemia cells. These effects are notably intensified when Flt3ITD is concurrently inhibited. Enasidenib therapy leads to leukemic cell differentiation, evidenced by an increased CD11b+ population and a decreased c-Kit+ population in the peripheral blood within 2 weeks[2].
体内研究
In an IDH2-mutant acute myeloid leukemia (AML) primary xenograft mouse model, treatment with enasidenib markedly enhances survival[1].
Acting as a mutant IDH2 inhibitor, enasidenib reconfigures the epigenetic landscape of IDH2-mutant cells, promoting changes in self-renewal and differentiation in an in vivo IDH2-mutant AML model. Treatment doses of 10 mg/kg or 100 mg/kg twice a day result in a significant reduction of 2-hydroxyglutarate (2-HG) levels, achieving a 96.7% decrease from baseline. Additionally, in mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells, treatment with enasidenib (100 mg/kg twice a day) significantly lowers 2-HG levels, aligning with the targeted inhibition of mutant IDH2, thus effectively blocking the production of 2-HG mediated by mutant IDH2[2].
体外研究
Enasidenib (AG-221) counteracts the alterations induced by mutant IDH2 on DNA methylation in mutant stem/progenitor cells, fostering differentiation and inhibiting the self-renewal capabilities of IDH2-mutant leukemia cells. These effects are notably intensified when Flt3ITD is concurrently inhibited. Enasidenib therapy leads to leukemic cell differentiation, evidenced by an increased CD11b+ population and a decreased c-Kit+ population in the peripheral blood within 2 weeks[2].
Enasidenib mesylate/恩西地平甲磺酸盐 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SW1353
49.47 μM
72 hours
SW1353 cells showed intermediate sensitivity to enasidenib
EBioMedicine. 2024 Apr;102:105090.
L2975
73.53 μM
72 hours
L2975 cells were partially resistant to enasidenib
EBioMedicine. 2024 Apr;102:105090.
CDS23
>100 μM
72 hours
CDS23 cells were fully resistant to enasidenib
EBioMedicine. 2024 Apr;102:105090.
CDS11
63.53 μM
72 hours
CDS11 cells were partially resistant to enasidenib
EBioMedicine. 2024 Apr;102:105090.
CDS17
16.65-22.65 μM
72 hours
Enasidenib significantly reduced the viability of CDS17 cells
EBioMedicine. 2024 Apr;102:105090.
KG-1 cells
5 μmol/L
Enasidenib inhibited proliferation and promoted apoptosis in AML wild-type cells. However, in IDH2 mutant AML cells, the inhibitory effect of Enasidenib on proliferation was not significant, nor did it significantly promote apoptosis.
Hematol Oncol. 2024 Nov;42(6):e3316.
HL-60 cells
5 μmol/L
Enasidenib inhibited proliferation and promoted apoptosis in AML wild-type cells. However, in IDH2 mutant AML cells, the inhibitory effect of Enasidenib on proliferation was not significant, nor did it significantly promote apoptosis.
Hematol Oncol. 2024 Nov;42(6):e3316.
IDH2-WT TF-1 erythroleukemic cell line
10 μM
8 days
Enasidenib enhanced erythroid differentiation of IDH2-WT TF-1 erythroleukemic cell line.
J Clin Invest. 2020 Apr 1;130(4):1843-1849.
CD34+ cells from normal human bone marrow
10 μM
8 days
Enasidenib enhanced erythroid differentiation of CD34+ cells from normal human bone marrow, as evidenced by increased proportion of CD71+GPA+ cells.
J Clin Invest. 2020 Apr 1;130(4):1843-1849.
CD34+ hematopoietic stem and progenitor cells (HSPCs)
1–25 μM
8 days
Enasidenib enhanced erythroid differentiation of CD34+ HSPCs, as evidenced by increased proportion and number of CD71+GPA+ cells in a dose-dependent manner.
J Clin Invest. 2020 Apr 1;130(4):1843-1849.
Enasidenib mesylate/恩西地平甲磺酸盐 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
T-CDS17#1 xenograft model
Oral
35 mg/kg
Twice a day for 21 days
Enasidenib completely inhibited tumor growth and caused tumor regression
EBioMedicine. 2024 Apr;102:105090.
Mice
Idh2R140QFlt3ITD mutant AML model
Oral
40mg/kg to 100mg/kg
Twice daily for 4 to 6 weeks
To evaluate the therapeutic effect of Enasidenib in vivo on Idh2R140QFlt3ITD mutant AML, showing reduction in serum 2HG levels, decreased proportion of cKit+ cells in peripheral blood, and partial restoration of bone marrow differentiation
Cancer Discov. 2017 May;7(5):494-505
Mice
IDH2 R140Q patient-derived xenografts
Oral
various doses
Continuous treatment for 10-20 days
AG-221 treatment resulted in upregulation of mature myeloid markers CD11b, CD14, CD15, and CD24, and a decrease in progenitor marker CD117, and differentiated cells retained the IDH2 R140Q mutation. In long-term survivors, blasts still persisted in the bone marrow with a significant mutant IDH2 allele burden.
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