| 名称 | CPI-169 racemate |
| 描述 | CPI-169 racemate (CPI 169) is a potent, and selective EZH2 inhibitor with IC50 of 0.24 nM, 0.51 nM, and 6.1 nM for EZH2 WT, EZH2 Y641N, and EZH1, respectively. |
| 细胞实验 | Relative cell numbers are assessed by Cell Titer-Glo (CTG) luminescent cell viability assay using an Envision instrument. GraphPad Prism 6.0 is used for curve fitting, IC50/GI50 and Hill coefficient (H) calculations. The GI90 is calculated using the formula: EC90 = (90 /100-90)1/H * EC50.(Only for Reference) |
| 激酶实验 | Biochemical Assays: Compound potency is also assessed through incorporation of 3H-SAM into a biotinylated H3 peptide. Specifically, PRC2 containing either EZH1 (160 pM), wt EZH2 (40 pM), or Y641N mutant EZH2 (80 pM, both EZH2 prepared in-house) is pre-incubated with 3H-SAM (0.9 μM), 2 μM H3K27me3 activating peptide (H2N-RKQLATKAAR(Kme3)SAPATGGVKKP-amide) and compounds (as 10 point duplicate dose response titrations) for 120 min in a buffer consisting of 50 mM Tris (pH 8.5), 1 mM DTT, 0.07 mM Brij-35, 0.1% BSA, and 0.8% DMSO in a total volume of 12.5 μl in a black 384 well plate. Reaction is initiated with biotinylated H3 substrate peptides (H3K27me1 for wt EZH2, H3K27me2 for Y641N mutant EZH2; H2N-RKQLATKAAR(Kmen)SAPATGGVKKP-NTPEGBiot) as a 2 μM stock in 12.5 μL and allowed to react at room temperature for 5 h. Quenching is accomplished by addition of 20 μl of STOP solution (50 mM Tris (pH 8.5), 200 mM EDTA, 2 mM SAH). 35 μL of the quenched solution is transferred to Streptavidin Flashplates, incubated overnight, washed, and read in a TopCount Reader. For titrations all compound dilutions are in DMSO, final DMSO concentrations are 0.8% (v/v), and turnover is kept to less than < 5%. IC50s are calculated using non-linear least square four parameter fits (GraphPad 6.0). |
| 动物实验 | Animal Models: Mice bearing KARPAS-422 subcutaneous xenograftsFormulation: 10% DMSO + 60% polytheylene glycol 400 + 30% ddH2ODosages: 200 mg/kg, BIDAdministration: s.c. |
| 体外活性 | 在KARPAS-422细胞中，CPI-169呈剂量依赖性地抑制细胞活力，并在与ABT-199联合使用时产生协同抗增殖活性。在25种NHL细胞系中的16种中，CPI-169还以GI50 <5 μM的效果抑制细胞生长。[1] |
| 体内活性 | 在携带KARPAS-422异种移植瘤的小鼠中，CPI-169（200 mg/kg, s.c.）有效降低了H3K27me3的水平，并导致淋巴瘤肿瘤的退缩，同时未影响体重或引起任何明显的不良反应。[1] |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 93 mg/mL (175.92 mM), Sonication is recommended.
DMSO : 93 mg/mL (175.92 mM), Sonication is recommended.
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| 关键字 | HistoneMethyltransferase | Histone Methyltransferase | EZH2 Y641N | EZH2 WT | EZH1 | EpigeneticReaderDomain | Epigenetic Reader Domain | CPI-169 racemate | CPI169 racemate | CPI 169 racemate |
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