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.
Cell Experiment | |
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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 | |
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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 |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[1] Daigle SR, et al. Blood. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
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