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EPZ-5676

Cat. No. M2179
EPZ-5676 Structure
Size Price Availability Quantity
5mg USD 120 In stock
10mg USD 180 In stock
50mg USD 600 In stock
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Quality Control
  • Current batch:
  • Purity >98%
  • COA
  • MSDS
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.

Protocol
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).
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 562.71
Formula C30H42N8O3
CAS Number 1380288-87-8
Purity >98%
Solubility DMSO
Storage at -20°C
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
Rating
References

Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
Daigle SR, et al. Blood. 2013 Aug 8;122(6):1017-25. PMID: 23801631.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: EPZ-5676 supplier, Histone Methyltransferase, inhibitors

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