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EPZ-5676 is a novel small molecule inhibitor of DOT1L. EPZ-5676 has an inhibition constant value of 80 pM, and demonstrates 37000-fold selectivity over all other methyltransferases tested. EPZ-5676 inhibits proliferation of MLL-AF4 rearranged cell line MV4-11 with an IC50 of 9 nM. EPZ-5676 reduces H3K79 dimethylation with a cellular IC50 of 2.6 nM in MV4-11 cells. EPZ-5676 blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is a potential treatment of MLL-rearranged leukemia and is under clinical investigation.
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Source | Clin Epigenetics (2017). Figure 5. EPZ-5676 |
| Method | immunoblotting | |
| Cell Lines | H358 cells | |
| Concentrations | 1 μM | |
| Incubation Time | 48 h | |
| Results | First, in order to evaluate the involvement of H3K79me3 in TGF-β1-induced EMT, A549 and H358 cells were treated with DOT1L inhibitors, EPZ5676 and SGC0946, simultaneously with TGF-β1 |
| Cell Experiment | |
|---|---|
| Cell lines | MV4-11 cells |
| Preparation method | Quantitative real-time polymerase chain reaction (qRT-PCR). To assess inhibition of HOXA9 and MEIS1 messenger RNA (mRNA) expression by EPZ-5676, exponentially growing MV4-11 cells were seeded in 75-cm2 culture flasks at 2 × 105 cells/mL and incubated in the presence of 0.2% DMSO or increasing concentrations of EPZ-5676. On day 4, cells were maintained in log phase culture by reseeding at 5 × 105 cells/mL and compound was replenished. On day 6, cells were harvested, total RNA extracted, and HOXA9 and MEIS1 mRNA levels assessed and normalized to the β2-microglobulin by qRT-PCR as previously described. |
| Concentrations | 0~1µM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | Rat MV4-11 xenograft models |
| Formulation | 5% hydroxypropyl-β-cyclodextrin in saline |
| Dosages | 70 mg/kg |
| Administration | IV infusion into the femoral vein continuously (24 hours/day), or intermittently (8 hours/day). |
| Molecular Weight | 562.71 |
| Formula | C30H42N8O3 |
| CAS Number | 1380288-87-8 |
| Solubility (25°C) | DMSO 60 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
[1] Daigle SR, et al. Blood. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
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