EPZ5676

Catalog No.S7062

EPZ-5676 is an S-adenosyl methionine (SAM) competitive inhibitor of protein methyltransferase DOT1L with Ki of 80 pM, demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor. Phase 1.

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EPZ5676 Chemical Structure

EPZ5676 Chemical Structure
Molecular Weight: 562.71

Validation & Quality Control

Quality Control & MSDS

Histone Methyltransferase Inhibitors with Unique Features

  • Most Potent DOT1L Inhibitor

    SGC 0946 DOT1L, IC50=0.3 nM.

  • FDA-approved Inhibitor

    Entacapone Approved by FDA for Parkinson's disease.

  • Newest HMT Inhibitor

    EPZ004777 Potent, selective DOT1L inhibitor with IC50 of 0.4 nM.

  • Classic HMT Inhibitor

    UNC1999 Potent, orally bioavailable and selective inhibitor of EZH2 and EZH1 with IC50 of 2 nM and 45 nM, respectively, showing >1000-fold selectivity over a broad range of epigenetic and non-epigenetic targets.

Product Information

  • Compare Histone Methyltransferase Inhibitors
    Compare Histone Methyltransferase Products
  • Research Area

Product Description

Biological Activity

Description EPZ-5676 is an S-adenosyl methionine (SAM) competitive inhibitor of protein methyltransferase DOT1L with Ki of 80 pM, demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor. Phase 1.
Targets DOT1L [1]
IC50 80 pM(Ki)
In vitro EPZ-5676 reduces H3K79 dimethylation with a cellular IC50 of 2.6 nM in MV4-11 cells. EPZ-5676 treatment results in concentration- and time-dependent reduction of H3K79 methylation without effect on the methylation status of other histone sites, which leads to inhibition of key MLL target genes and selective, apoptotic cell killing in MLL-rearranged leukemia cells. EPZ-5676 inhibits proliferation of MLL-AF4 rearranged cell line MV4-11 with an IC50 of 9 nM.
In vivo EPZ-5676 continuously intravenous infusion for 21 days to xenograft model of MLL-rearranged leukemia, leads to dose-dependent anti-tumor activity. At the highest dose of 70.5 mg/kg/day, complete tumor regressions are achieved with no regrowth for up to 32 days after the cessation of treatment. No significant weight loss or obvious toxicity is observed in rats treated with EPZ-5676 during efficacy study.
Features

Protocol(Only for Reference)

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Robert A. Protein methyltransferases in cancer. AACR Annual Meeting, 2013.

[2] Pollock RM, 54th ASH Annual Meeting and Exposition, 2012, Abst 2379

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02141828 Recruiting Leukemia|Acute Myeloid Leukemia|Acute Lymphocytic Leukemia|Acute Leukemias Epizyme, Inc.|Celgene Corporation May 2014 Phase 1
NCT01684150 Recruiting Acute Myeloid Leukemia|Acute Lymphoblastic Leukemia|Myelodysplastic Syndrome|Myeloproliferative Disorders|Chronic Myeloid Leukemia Epizyme, Inc.|Celgene Corporation September 2012 Phase 1

Chemical Information

Molecular Weight (MW) 562.71
Formula

C30H42N8O3

CAS No. 1380288-87-8
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL (177 mM)
Water <1 mg/mL (<1 mM)
Ethanol 100 mg/mL (177 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 9H-Purin-6-amine, 9-[5-deoxy-5-[[cis-3-[2-[6-(1,1-dimethylethyl)-1H-benzimidazol-2-yl]ethyl]cyclobutyl](1-methylethyl)amino]-β-D-ribofuranosyl]-

Research Area

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Tel: +1-832-582-8158 Ext:3

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