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532282 DOT1L Inhibitor, EPZ004777 - CAS 1338466-77-5 - Calbiochem

532282
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Key Specifications Table

Empirical FormulaCAS #
C₂₈H₄₁N₇O₄ 1338466-77-5

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      Description
      OverviewA cell-permeable, non-toxic, a near chemical derivative of S-adenosylmethionine (SAM) that competitively binds to the SAM-binding pocket of DOT1L and inhibits its activity in a reversible manner (IC50 = 400 pM; Ki = 300 pM). Shown to inhibit the methylation of cellular H3K79 in MLL cells and block the expression of leukemogenic genes. Displays excellent selectivity over other histone methyltransferases PRMT5 (IC50 = 521 nM), CARM1, EHMT2, EZH1, EZH2, PRMT1, PRMT8, SETD7 and WHSC1 (IC50 > 50 µM). Inhibits the proliferation of MV4-1, MOLM-13, KOPN-8 cells (IC50 = 170, 720, and 620 nM, respectively) and suppresses the growth of MV4-11 xenografts in nude mice model (50 mg/ml, s.c. minipump infusion). Blocks the cell cycle at G0/G1 phase and induces apoptotic cell death by activating caspase 3/7. Also shown to accelerate reprogramming of somatic cells into induced pluripotent stem cells.

      Please note that the molecular weight for this compound is batch-specific due to variable water content.
      Catalogue Number532282
      Brand Family Calbiochem®
      SynonymsEPZ4777, 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl), HMTase Inhibitor XVI
      References
      ReferencesDaigle, S.R., et al. 2013. Blood. 122, 1017.
      Yu, W., et al. 2012. Nat. Commun. 3, 1288.
      Daigle, S.R., et al. 2011. Cancer Cell. 20, 53.
      Product Information
      CAS number1338466-77-5
      FormWhite powder
      Hill FormulaC₂₈H₄₁N₇O₄
      Chemical formulaC₂₈H₄₁N₇O₄
      Hygroscopic Hygroscopic
      ReversibleY
      Quality LevelMQ100
      Applications
      Biological Information
      Primary TargetDOT1L
      Primary Target IC<sub>50</sub>400 pM
      Primary Target K<sub>i</sub>300 pM
      Purity≥97% by HPLC
      Physicochemical Information
      Cell permeableY
      Dimensions
      Materials Information
      Toxicological Information
      Safety Information according to GHS
      Safety Information
      Product Usage Statements
      Storage and Shipping Information
      Ship Code Ambient Temperature Only
      Toxicity Standard Handling
      Storage -20°C
      Protect from Light Protect from light
      Hygroscopic Hygroscopic
      Do not freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
      Packaging Information
      Packaged under inert gas Packaged under inert gas
      Transport Information
      Supplemental Information
      Specifications

      Documentation

      DOT1L Inhibitor, EPZ004777 - CAS 1338466-77-5 - Calbiochem SDS

      Title

      Safety Data Sheet (SDS) 

      References

      Reference overview
      Daigle, S.R., et al. 2013. Blood. 122, 1017.
      Yu, W., et al. 2012. Nat. Commun. 3, 1288.
      Daigle, S.R., et al. 2011. Cancer Cell. 20, 53.

      Brochure

      Title
      NPI Flyer- Epigenetics and Nuclear Function Feature (EMD)
      New Products - Antibodies, Small Molecule, Inhibitors

      Technical Info

      Title
      White Paper: Further considerations of antibody validation and usage. (EMD)
      Data Sheet

      Note that this data sheet is not lot-specific and is representative of the current specifications for this product. Please consult the vial label and the certificate of analysis for information on specific lots. Also note that shipping conditions may differ from storage conditions.

      Revision19-December-2014 JSW
      SynonymsEPZ4777, 1-(3-((((2R,3S,4R,5R)-5-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(isopropyl)amino)propyl)-3-(4-(tert-butyl)phenyl), HMTase Inhibitor XVI
      DescriptionA cell-permeable S-adenosylmethionine (AdoMet/SAM) structural derivative that potently inhibits DOT1L methyltransferase activity (IC50 = 400 pM) in a SAM-competitive (Ki = 300 pM) manner via a 1:1 stoichiometric interaction (KD = 250 pM), not only blocking DOT1L SAM-binding site with its deazaadenosine moiety, but also disrupting the overall structural integrity of the catalytic pocket with its tert-butylphenyl moiety, while inhibiting PRMT5 only at much higher concentrations (IC50 = 521 nM or 25 µM, respectively, using free or MEP50-complexed PRMT5) and exhibiting little potency against CARM1, EHMT2, EZH1, EZH2, PRMT1, PRMT8, SETD7, or WHSC1 even at a high concentration of 50 µM. Although EPZ004777 effectively inhibits cellular H3K79 methylation regardless of MLL translocation status (ICmax ~3 µM post 4 d treatment in MV4-11, MOLM-13, and Jurkat cells with MLL-AF4, MLL-AF9, and no MLL rearrangement, respectively), the viability of MLL rearranged cells are more susceptible to EPZ004777 treatment (IC50 = 0.62 to 6.74 µM in cultures with MLL-AF4, MLL-AF9, or MLL-ENL fusion; GI50 =13.9 µM to no inhibition at 50 µM in cultures with no MLL rearrangement; by Guava ViaCount Assay/4000-0040 at the end of 14 to 18 treatment period; cells split with fresh media/inhibitor every 3-4 d) due to effective transcription blockage of MLL fusion target genes (IC50 ~700 nM in reducing HOXA9 & MEIS1 mRNA levels in MV411 & MOLM-13 cultures). Despite poor pharmacokinetic properties, continuous EPZ004777 infusion via subcutaneously implanted osmotic pumps (100 mg/mL & 150 mg/mL to achieve steady state plasma drug conc of 0.64 & 0.84 µM, respectively) is reported to significantly extend the survival of NSG mice received MV4-11 cells via tail vein injection (100% death on d11 or d17 post 14 d vehicle or drug infusion period, respectively).
      FormWhite powder
      Intert gas (Yes/No) Packaged under inert gas
      CAS number1338466-77-5
      Chemical formulaC₂₈H₄₁N₇O₄
      Purity≥97% by HPLC
      SolubilityDMSO (50 mg/ml). Insoluble in H₂O. Use only fresh DMSO for reconstitution.
      Storage -20°C
      Hygroscopic
      Protect from light
      Do Not Freeze Ok to freeze
      Special InstructionsFollowing reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
      Toxicity Standard Handling
      ReferencesDaigle, S.R., et al. 2013. Blood. 122, 1017.
      Yu, W., et al. 2012. Nat. Commun. 3, 1288.
      Daigle, S.R., et al. 2011. Cancer Cell. 20, 53.