CX-4945 (Silmitasertib)是一种有效的，选择性CK2(casein kinase 2)抑制剂，IC50为1 nM，对Flt3， Pim1和CDK1作用效果稍弱(在细胞实验中无活性)。
别名：Silmitasertib; CX-4945
CX-4945 (Silmitasertib)是一种有效的，选择性CK2(casein kinase 2)抑制剂，IC50为1 nM，对Flt3， Pim1和CDK1作用效果稍弱(在细胞实验中无活性)。CX-4945是CK2特异的抑制剂，它只抑制238种激酶中的7种并且在0.5 μM浓度时它的抑制率超过90%，这是CK2的IC50的500多倍。虽然在无细胞系统中CX-4945抑制FLT3, PIM1和CDK1的IC50分别为35 nM, 46 nM和56 nM，但是在细胞基础上的功能实验中10 μM的CX-4945对FLT3, PIM1和 CDK1抑制作用不强。CX-4945有广谱的抗恶性细胞增生活性。
Sci Rep. 2017 Dec 14;7(1):17569.
CK2 modulates adipocyte insulinsignaling and is up-regulated in human obesity
UNIVERSITA’ DEGLI STUDI DI PADOVA. 2017.
Biochim Biophys Acta. 2015 Jul;1853(7):1693-701.
Protein kinase CK2 potentiates translation efficiency by phosphorylating eIF3j at Ser127.
Biomed Res Int. 2015;601543.
Phosphorylation, Signaling, and Cancer: Targets and Targeting.
Growth Factors. 2015 Sep 04;259-266.
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数据来源 | Sci Rep (2017). Figure 4. CX-4945 (AbMole BioScience, Hong Kong, China) |
| 方法 | ip inject | |
| 细胞系/动物模型 | C57BL6/6 J (B6) male mice | |
| 浓度 | 20 mg/kg | |
| 处理时间 | 2 h | |
| 实验结果 | CK2 activity and Akt-signaling were then evaluated in insulin-target tissues. Insulin-treatment did not affect the basal kinase activity of different tissues, while CX-4945 injection strikingly inhibited CK2 in VAT-E, SAT and liver |
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数据来源 | Sci Rep (2017). Figure 2. CX-4945 (AbMole BioScience, Hong Kong, China) |
| 方法 | Weatern Blot | |
| 细胞系/动物模型 | human adipocyte | |
| 浓度 | 2.5 μM | |
| 处理时间 | 1 h | |
| 实验结果 | Results obtained in 3T3-L1 cells were confirmed in human adipocyte primary cultures, where CX-4945 and DMAT pre-treatment substantially inhibited the insulin-stimulated glucose uptake |
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数据来源 | Sci Rep (2017). Figure 1. CX-4945 (AbMole BioScience, Hong Kong, China) |
| 方法 | Weatern Blot | |
| 细胞系/动物模型 | human adipocyte | |
| 浓度 | 2.5 μM | |
| 处理时间 | 1 h | |
| 实验结果 | Conversely, a great reduction of insulin-induced glucose uptake was observed in 3T3-L1 mature adipocytes, pre-treated for 1 h with the CK2-inhibitor CX-494528 and then stimulated with increasing insulin doses for 30 min |
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数据来源 | Biomed Res Int (2015). Figure 5. CX-4945 (Abmole Bioscience) |
| 方法 | Wound-Healing Assays | |
| 细胞系/动物模型 | U2OS cells | |
| 浓度 | 3 µM | |
| 处理时间 | 24 h | |
| 实验结果 | Both CX-4945 and TDB were able to inhibit cell motility in 24–48 h assayswhen cellswere constantly exposed to them (upper part of the figure). |
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数据来源 | Biomed Res Int (2015). Figure 4. CX-4945 (Abmole Bioscience) |
| 方法 | Wound-Healing Assays | |
| 细胞系/动物模型 | U2OS cells | |
| 浓度 | 3 µM | |
| 处理时间 | 24 h | |
| 实验结果 | We found that TDB-treated cells were much less prone than vehicle-treated cells to forming spheroids, while CX-4945 was similarly effective than TDB when assessed at 24h but has much weaker effect at longer times after the inhibitor removal. |
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数据来源 | Biomed Res Int (2015). Figure 3. CX-4945 (Abmole Bioscience) |
| 方法 | Wound-Healing Assays | |
| 细胞系/动物模型 | U2OS cells | |
| 浓度 | 3 µM | |
| 处理时间 | 24 h | |
| 实验结果 | The results, shown in Figure 3, indicate that TDB is much more effective than CX-4945 in preventing clone formation and survival. |
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数据来源 | Biomed Res Int (2015). Figure 2. CX-4945 (Abmole Bioscience) |
| 方法 | Western Blot | |
| 细胞系/动物模型 | CEM or U2OS cells | |
| 浓度 | 3 µM | |
| 处理时间 | 24h, 48h, 72h, 96h | |
| 实验结果 | The results, shown in Figure 2(b), demonstrated that the phosphorylation of Akt1 Ser129 is similarly reduced by the two inhibitors immediately after treatment, while it remains significantly lower than the control only with TDB in case of inhibitor removal, thus confirming the more permanent blockage of the kinase activity by TDB than by CX-4945. |
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数据来源 | Biomed Res Int (2015). Figure 1. CX-4945 (Abmole Bioscience) |
| 方法 | Comparison of CX-4945 and TDB efficacy on cellular CK2 activity. | |
| 细胞系/动物模型 | CEM or U2OS cells | |
| 浓度 | 1 µM | |
| 处理时间 | 4 h | |
| 实验结果 | To compare the inhibitory efficacy in cells of the two compounds, CX-4945 and TDB, we analyzed their effects on two cell lines, one deriving from a blood tumor (CEM, T-cell lymphoblastoma) and the other from a solid tumor (U2OS, osteosarcoma). Their efficacy was quite similar in inhibiting cellular CK2. |
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数据来源 | Growth Factors (2015) . Figure 6.CX-4945 was from AbMole Bioscience (Houston, TX). |
| 方法 | western blot | |
| 细胞系/动物模型 | fibroblasts from N, T1DM , and T1DM+ | |
| 浓度 | 10 µM | |
| 处理时间 | 72h | |
| 实验结果 | Although we cannot strictly confirm that all the bands shown in the WB of Figure 6 are direct targets of CK2, our observations suggest that the three cell groups might differ in some regulatory mechanisms which depend on CK2 and can be affected by its blockage. |
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数据来源 | Growth Factors (2015) . Figure 5.CX-4945 was from AbMole Bioscience (Houston, TX). |
| 方法 | western blot | |
| 细胞系/动物模型 | fibroblasts from N, T1DM , and T1DM+ | |
| 浓度 | 10 µM | |
| 处理时间 | 72h | |
| 实验结果 | "we did not find any significant difference of phosphorylation level of a CK2 crucial target, Akt Ser129 among the three cell groups. Also the expression of the total Akt protein was very similar among groups (Figure 5). However, as shown in Figure 5, both CX-4945 and TBB treatment produced a reduction of Sp129-Akt phosphorylation to a level that was very similar among the three groups of cells." |
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数据来源 | Growth Factors (2015) . Figure 3.CX-4945 was from AbMole Bioscience (Houston, TX). |
| 方法 | Cell viability assay | |
| 细胞系/动物模型 | fibroblasts from N, T1DM , and T1DM+ | |
| 浓度 | 10 and 20 µM | |
| 处理时间 | 48 h and 72 h | |
| 实验结果 | The results substantially confirmed those obtained with TBB, showing in addition that the fibroblasts from T1DM+ patients were the most sensitive among the subjects’ groups (Figure 3a), their viability being significantly reduced already at the lower dose (10 mM of CX-4945) within 48 h. |
-3.jpg) |
数据来源 | Biochimica et Biophysica Acta (2015) . Figure 4.CX-4945 was purchased from AbMole BioScience (Hong Kong, China. |
| 方法 | western blot and Immunoprecipitation(IP) | |
| 细胞系/动物模型 | HEK293 | |
| 浓度 | 2.5µM | |
| 处理时间 | 5 h | |
| 实验结果 | CK2 inhibitor CX-4945 induces the dissociation of a large amount of j-subunit from the eIF3 complex both bound or unbound to the 40S subunits and its shift toward the low-density region of the gradient, where CK2α and CK2β are also detectable (fractions 11–14). |
-2.jpg) |
数据来源 | Biochimica et Biophysica Acta (2015) . Figure 3.CX-4945 was purchased from AbMole BioScience (Hong Kong, China. |
| 方法 | western blot and Immunoprecipitation(IP) | |
| 细胞系/动物模型 | HEK293 | |
| 浓度 | 2.5µM | |
| 处理时间 | 5 h | |
| 实验结果 | CX-4945 and Q1 strongly reduce the phosphorylation extent of Akt1 Ser129, a specific target of CK2 (about 80% and 65%, respectively), while they do not change the protein-level of CK2α, CK2β and eIF3j(wb).CX-4945 or quinalizarin does not affect the interaction of the kinase with the eIF3 subunits eIF3b and eIF3d, it causes an about 3-fold increase of eIF3j co-immuniprecipitation(IP). |
-1.jpg) |
数据来源 | Biochimica et Biophysica Acta (2015) . Figure 1.CX-4945 was purchased from AbMole BioScience (Hong Kong, China. |
| 方法 | Immunoprecipitation(IP) | |
| 细胞系/动物模型 | HEK293, Hela, LAMA84 | |
| 浓度 | 0.5µM | |
| 处理时间 | 15 min | |
| 实验结果 | The strong inhibition of the 33P-phosphorylation induced by in vitro addition of the CK2 selective and potent inhibitor CX-4945. The kinase co-immunoprecipitated with eIF3j specifically phosphorylates the subunit as demonstrated by the strong reduction of the eIF3j 33P phosphorylation caused by in vitro addition of the CK2 inhibitor CX-4945. |
| 体外实验* | |
|---|---|
| 细胞系 | BT-474 (breast) or BxPC-3 (pancreatic) cancer or HUVEC cells |
| 方法 | A 5 mmol/L stock solution in dimethyl sulfoxide was prepared and stored at - 70 ℃. The drug was diluted directly into growth media immediately prior to use.Various cell lines were seeded at a density of 3,000 cells per well 24 hours prior to treatment, in appropriate media, and then treated with indicated concentrations of CX-4945. Suspensions cells were seeded and treated on the same day.Following 4 days of incubation, Alamar Blue (20 mL, 10% of volume per well) was added and the cells were further incubated at 37 C for 4–5 hours. Fluorescence with excitation wavelength at 530–560 nm and emission wavelength at 590 nm was measured. |
| 浓度 | 0, 0.1, 1.0, 5.0, 10 µM |
| 处理时间 | 24 h |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 体内实验* | |
|---|---|
| 动物模型 | Female immunocompromised mice CrTac:Ncr-Foxn1nu (5–7 weeks old) BT474 or BxPC-3 cells Xenografts |
| 配制 | Solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide (Sigma-Aldrich) and 6% Solutol (Sigma-Aldrich). |
| 剂量 | twice daily at 25 or 75 mg/kg for 31 and 35 consecutive days |
| 给药处理 | oral gavage |
*上述方法来自公开文献，仅供相同目的实验参考。如实验目的、材料、方法不同，请参考其他文献。
| 分子量 | 349.77 |
| 分子式 | C19H12ClN3O2 |
| CAS号 | 1009820-21-6 |
| 溶解性（25°C） | DMSO ≥ 46 mg/mL |
| 储存条件 |
粉末型式 -20°C 3年；4°C 2年 溶于溶剂 -80°C 6个月；-20°C 1个月 |
| 运输方式 | 冰袋运输，根据产品的不同，可能会有相应调整。 |
*下述溶液配置方法仅为基于分子量计算出的理论值。不同产品在配置溶液前，需考虑其在不同溶剂中的溶解度限制。
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 2.859 mL | 14.2951 mL | 28.5902 mL |
| 5 mM | 0.5718 mL | 2.859 mL | 5.718 mL |
| 10 mM | 0.2859 mL | 1.4295 mL | 2.859 mL |
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 | |
| 重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| 体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km 系数 | 3 | 6 | 12 | 8 | 5 | 20 |
| 动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
| 动物 A的Km系数 |
例如，依据体表面积折算法，将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量，需要将20 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到化合物用于大鼠的等效剂量为10 mg/kg。
[3] Ferguson et al. FEBS Lett. Structural basis of CX-4945 binding to human protein kinase CK2.
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