EPZ004777 is a potent, selective, small-molecule inhibitor of DOT1L with IC50 of 0.4 nM. EPZ004777 selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. EPZ004777 suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1, and selectively impaired proliferation of MLL-AF10 and CALM-AF10 transformed cells. In vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model.
|Source||Cell Death Dis (2018). Figure 2. EPZ004777|
|Method||Bone resorption assay|
|Cell Lines||RAW264.7 cells|
|Incubation Time||60 h|
|Results||Furthermore, no significant difference was observed between the effects of treatment at 1 and 10 μM of the DOT1L inhibitors. In bone resorption assays, both EPZ5676 and EPZ004777 increased the resorption pit area at 1 and 10 μM concentrations|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO 100 mg/mL
Ethanol 100 mg/mL
Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.
Deshpande AJ, et al. Blood. 2013 Mar 28;121(13):2533-41. PMID: 23361907.
Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l.
Chen L, et al. Leukemia. 2013 Apr;27(4):813-22. PMID: 23138183.
Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.
Daigle SR, et al. Cancer Cell. 2011 Jul 12;20(1):53-65. PMID: 21741596.
|Related Histone Methyltransferase Products|
WDR5-0103 is a small molecule that binds a peptide-binding pocket on WDR5 (Kd = 450 nM), inhibiting the catalytic activity of the MLL core complex in vitro (IC50 = 39 µM).
MS023 is a potent and selective, cell-active inhibitor of type I PRMTs with IC50s of 4-119 nM.
BIX-01294 is a potent chemical inhibitor of G9a methyltransferase that catalyzes the mono-and di-methylation of the lysine 9 residue of histone H3, with IC50 of 1.9 μM.
EPZ011989 is a potent, orally-available EZH2 inhibitor with Ki < 3 nM for EZH2 wt and EZH2 Y646.
SGC0946 is a highly potent and selective DOT1L methyltransferase inhibitor with IC50 of 0.3 nM; selectively kill mixed lineage leukaemia cells.
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