EPZ004777
EPZ004777 is a specific small-molecule H3K79 methyltransferase DOT1L inhibitor that potently inhibits DOT1L in a radionuclide homogeneous assay with the half maximal inhibition concentration IC50 value of 400 pM and selectively kills a variety of MLL-rearranged leukemia cells, including an MLL-AF4 leukemia cell line MV4-11 and an MLL-AF9 leukemia cell line MOLM13 [1 & 2].
EPZ004777 has also been found to selectively inhibit the proliferation of MLL-AF10 and CALM-AF10 transformed cells in a dose dependent manner (IC50: 0.1 μM to 1 μM), in which the mRNA expression levels of two hallmark leukemogenic genes (Hoxa9 and Meis1) are suppressed by EPZ004777 in a concentration dependent manner [2].
Reference
References:
[1] Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J, Marcellus R, Iacob RE, Engen JR, Griffin C, Aman A, Wienholds E, Li F, Pineda J, Estiu G, Shatseva T, Hajian T, Al-Awar R, Dick JE, Vedadi M, Brown PJ, Arrowsmith CH, Bradner JE, Schapira M. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288. doi: 10.1038/ncomms2304.
[2] Chen L, Deshpande AJ, Banka D, Bernt KM, Dias S, Buske C, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013 Apr;27(4):813-22. doi: 10.1038/leu.2012.327. Epub 2012 Nov 9.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 539.67 |
| Cas No. | 1338466-77-5 |
| Formula | C28H41N7O4 |
| Solubility | ≥27 mg/mL in DMSO; insoluble in H2O; ≥94.6 mg/mL in EtOH with ultrasonic |
| Chemical Name | 1-[3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxyoxolan-2-yl]methyl-propan-2-ylamino]propyl]-3-(4-tert-butylphenyl)urea |
| SDF | Download SDF |
| Canonical SMILES | CC(C)N(CCCNC(=O)NC1=CC=C(C=C1)C(C)(C)C)CC2C(C(C(O2)N3C=CC4=C3N=CN=C4N)O)O |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment[1]: | |
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Cell lines |
Human leukaemia cell line MV4;11 and Molm13 cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
96 h, 10 μM |
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Applications |
EPZ004777 is a specific and potent inhibitor of DOT1L with IC50 values of 400 pM in a radionuclide homogeneous assay. It selectively kills mixed lineage leukaemia cells, in which DOT1L interacts with oncogenic MLL fusion protein and is unconventionally localized. |
| Animal experiment [2]: | |
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Animal models |
Eight-week-old C57BL/6 mice |
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Dosage form |
Mice were implanted with osmotic pumps loaded with vehicle(15% ethanol, 50% PEG300, 35% water) or EPZ004777 at 150 mg/ml. One week later, osmotic pumps were replaced and retained for another week. |
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Application |
EPZ004777 is well tolerated and no obvious toxicity is observed in mice. EPZ004777 has both antitumor and pharmacodynamic efficacy in the mouse xenograft model of MLL leukemia. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Yu W, Chory E J, Wernimont A K, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors[J]. Nature communications, 2012, 3: 1288. [2]. Daigle S R, Olhava E J, Therkelsen C A, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor[J]. Cancer cell, 2011, 20(1): 53-65. |
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Quality Control & MSDS
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Chemical structure
