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EPZ-5676

Cat. No. M2179
EPZ-5676 Structure
Synonym:

Pinometostat

Size Price Availability Quantity
5mg USD 70  USD70 In stock
10mg USD 100  USD100 In stock
25mg USD 210  USD210 In stock
50mg USD 360  USD360 In stock
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Quality Control & Documentation
Biological Activity

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.

Customer Product Validations & Biological Datas
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
Protocol (for reference only)
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).
Chemical Information
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
Conversion of different model animals based on BSA (PMID: 27057123)
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.

References

[1] Daigle SR, et al. Blood. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

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Keywords: EPZ-5676, Pinometostat supplier, Histone Methyltransferase, inhibitors, activators


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