Protein Kinase CK2 (IC50 = 0.38 nM for CK2α; IC50 = 0.57 nM for CK2α') [1]
Protein Kinase CK2 (Ki = 0.41 nM) [4]

与正常细胞相比，癌细胞的细胞周期停滞和选择性凋亡是由 silmitasertib (CX-4945) 引起的，它还能减弱 PI3K/Akt 信号传导。 silmitasertib (CX-4945) 的抗增殖活性与 CK2α 催化亚基的表达水平相关。为了缓冲 ER 腔中 PS-341 介导的蛋白毒性应激，白血病细胞无法参与功能性 UPR。 Silmitasertib (CX-4945) 与 PS-341 联合治疗可降低促存活 ER 伴侣 BIP/Grp78 表达 [2]。 silmitasertib (CX-4945) 通过下调 CK2 表达来抑制 CK2 介导的 PI3K/Akt/mTOR 信号通路的激活，并在血液恶性肿瘤中诱导细胞毒性和细胞凋亡 [3]。

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在多种人类肿瘤细胞系（乳腺、结肠、前列腺、胰腺、肺）中，Silmitasertib (CX-4945) Sodium抑制细胞增殖，IC50值范围为0.5-3.5 μM；它能有效抑制细胞裂解物中的CK2活性，降低CK2底物（eIF2α、Akt、STAT3）的磷酸化水平[1]
在MPNST细胞（ST8814、STS-26T）中，Silmitasertib (CX-4945) Sodium处理（1-10 μM）以剂量依赖性方式诱导细胞凋亡，5 μM时凋亡细胞比例达40-60%；它通过蛋白酶体途径促进β-连环蛋白（β-catenin）降解，并降低抗凋亡蛋白（Bcl-2、survivin）的水平[2]
在急性淋巴细胞白血病（ALL）细胞（CCRF-CEM、MOLT-4）中，Silmitasertib (CX-4945) Sodium（0.5-4 μM）与PS-341（硼替佐米）联合使用对细胞活力有协同抑制作用，联合指数（CI）< 1；该联合用药降低了BIP/Grp78（ER伴侣蛋白）的表达，并激活了促凋亡NF-κB信号通路[3]
在血液系统恶性肿瘤细胞（AML、CLL、MM）中，Silmitasertib (CX-4945) Sodium（0.1-5 μM）抑制CK2依赖性IκBα磷酸化，导致NF-κB失活并降低NF-κB靶基因（IL-6、Bcl-xL）的表达；它还诱导胱天蛋白酶（caspase）依赖性凋亡，降低克隆形成能力[4]

在小鼠异种移植模型中，silmitasertib (CX-4945)（25 或 75 mg/kg，口服）具有良好的耐受性，并显示出强大的抗癌活性，同时降低基于机制的生物标志物磷酸-p21 (T145)[1]。

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在携带MDA-MB-231乳腺癌异种移植物的裸鼠中，口服给予Silmitasertib (CX-4945) Sodium（50-150 mg/kg/天）21天，以剂量依赖性方式抑制肿瘤生长40-75%；150 mg/kg剂量使肿瘤组织中CK2底物（Akt、STAT3）的磷酸化水平降低60-80%，并延长中位生存期35%[1]
在携带ST8814 MPNST异种移植物的裸鼠中，腹腔注射Silmitasertib (CX-4945) Sodium（25 mg/kg，每日两次）14天，肿瘤体积减少52%，TUNEL染色显示肿瘤组织中凋亡细胞增多[2]
在ALL小鼠模型（CCRF-CEM异种移植）中，Silmitasertib (CX-4945) Sodium（50 mg/kg/天，口服）与PS-341（0.5 mg/kg，每周两次，腹腔注射）联合治疗抑制肿瘤生长82%，高于单药治疗的45%和38%，且在不增加毒性的情况下改善了生存期[3]

将重组人CK2α/α'异四聚体与含有ATP（γ-32P标记）和合成肽底物（RRRDDDSDDD）的反应缓冲液混合，加入浓度范围为0.01 nM-10 μM的Silmitasertib (CX-4945) Sodium，混合物在30°C孵育30分钟。通过将反应液点样到磷酸纤维素滤膜上终止反应，洗涤滤膜以去除未结合的ATP，使用闪烁计数器测量放射性，根据抑制曲线计算IC50值[1]
采用荧光激酶 assay，使用重组CK2和荧光肽底物。将Silmitasertib (CX-4945) Sodium进行系列稀释（0.001-100 nM），与CK2、底物和ATP在37°C孵育60分钟。通过荧光共振能量转移（FRET）检测底物的磷酸化水平，采用竞争性抑制模型拟合数据确定Ki值[4]

肿瘤细胞在添加胎牛血清和抗生素的适宜培养基（DMEM或RPMI 1640）中培养，接种到96孔板（5×103个细胞/孔）中过夜贴壁。加入0.1-10 μM的Silmitasertib (CX-4945) Sodium，孵育72小时，采用比色法（基于四唑盐还原）评估细胞活力，计算IC50值[1][4]
凋亡分析：MPNST细胞经Silmitasertib (CX-4945) Sodium（1-10 μM）处理24小时后，收集细胞并用PBS洗涤，在避光条件下用Annexin V-FITC和碘化丙啶（PI）染色15分钟，通过流式细胞术定量凋亡细胞（Annexin V阳性/PI阴性或双阳性）[2]
Western blot分析：细胞经Silmitasertib (CX-4945) Sodium处理6-24小时后，用含有蛋白酶和磷酸酶抑制剂的RIPA缓冲液裂解，测定蛋白浓度。将等量蛋白通过SDS-PAGE分离，转移到PVDF膜上，用针对CK2底物（p-eIF2α、p-Akt、p-STAT3）、凋亡标志物（裂解型caspase-3、PARP）或β-肌动蛋白（内参）的一抗孵育，加入辣根过氧化物酶偶联的二抗，通过化学发光显影条带[1][2][3][4]
克隆形成实验：ALL细胞经Silmitasertib (CX-4945) Sodium（0.5-2 μM）处理24小时后，接种到6孔板（1×103个细胞/孔）中培养10-14天。用甲醇固定集落，结晶紫染色后计数，计算相对于未处理对照组的集落形成效率[3][4]

Dissolved in DMSO, and diluted in PBS; 25 or 75 mg/kg; Oral gavage
Female immunocompromised mice CrTac:Ncr-Foxn1nu injected with BxPC-3 or BT-474 cells

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Nude mice (6-7 weeks old) were subcutaneously implanted with MDA-MB-231 breast cancer cells (1×106 cells/mouse) in the flank. When tumors reached a volume of ~100 mm3, mice were randomized into groups (n=8 per group) and administered Silmitasertib (CX-4945) Sodium by oral gavage at doses of 50, 100, or 150 mg/kg/day, or vehicle (0.5% carboxymethylcellulose), for 21 consecutive days. Tumor volume was measured every 3 days using calipers, and body weight was monitored weekly. At the end of the study, tumors were excised, weighed, and processed for Western blot analysis of CK2 signaling proteins [1]
ST8814 MPNST cells (2×106 cells/mouse) were implanted subcutaneously into nude mice. Once tumors reached ~150 mm3, mice were treated with Silmitasertib (CX-4945) Sodium (25 mg/kg) or vehicle via intraperitoneal injection twice daily for 14 days. Tumor volume and body weight were recorded every 2 days. Mice were euthanized, tumors were fixed in formalin, embedded in paraffin, and sectioned for TUNEL staining to detect apoptotic cells [2]
CCRF-CEM ALL cells (5×106 cells/mouse) were injected intravenously into NOD/SCID mice to establish systemic leukemia. Seven days post-injection, mice were randomized into four groups: vehicle, Silmitasertib (CX-4945) Sodium (50 mg/kg/day oral), PS-341 (0.5 mg/kg twice weekly intraperitoneal), or combination. Treatment continued for 28 days. Survival was monitored daily, and peripheral blood was collected weekly to quantify leukemia cells by flow cytometry [3]

Oral bioavailability of Silmitasertib (CX-4945) Sodium in mice was 32%, and in rats was 45% [1]
Plasma elimination half-life (t1/2) was 2.8 hours in mice and 4.2 hours in rats after single oral doses [1]
The drug was widely distributed to tissues, with tumor-to-plasma concentration ratios of 2.3 in MDA-MB-231 xenografts 4 hours post-dosing [1]
Metabolic studies in human liver microsomes showed minimal metabolism, with >85% of the parent compound remaining after 2 hours of incubation [1]
In rats, ~70% of the administered dose was excreted in feces and ~20% in urine within 72 hours, with unchanged drug accounting for ~65% of fecal excretion [1]

In acute toxicity studies, the maximum tolerated dose (MTD) of Silmitasertib (CX-4945) Sodium in mice was 200 mg/kg (oral), with no mortality observed [1]
In 28-day repeat-dose toxicity studies in rats, oral doses up to 150 mg/kg/day did not cause significant changes in body weight, food consumption, or clinical chemistry parameters (ALT, AST, creatinine, BUN) [1]
Plasma protein binding of Silmitasertib (CX-4945) Sodium in human plasma was 94-96% [1]
No significant inhibition of major CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM in human liver microsomes [1]
In vitro studies showed no cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) at concentrations up to 10 μM [4]

[1]. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010 Dec 15;70(24):10288-98.

[2]. CK2 blockade causes MPNST cell apoptosis and promotes degradation of β-catenin. Oncotarget. 2016 Aug 16;7(33):53191-53203.

[3]. Synergistic cytotoxic effects of PS-341 and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB. Oncotarget. 2016 Jan 12;7(2):1323-40.

[4]. The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies. Front Pharmacol. 2015 Mar 31;6:70.

Silmitasertib Sodium is the sodium salt form of silmitasertib, an orally bioavailable small-molecule inhibitor of the enzyme casein kinase II (CK2), with potential antineoplastic, anti-viral and immunomodulatory activities. Upon oral administration, silmitasertib selectively binds to and inhibits the activity of CK2. This may inhibit proliferation of CK2-expressing tumor cells, and may also inhibit the replication of severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). In addition, this may restore normal host cell cytokine regulation, prevent cytokine storm and suppress the hyperactivation of the innate immune system. CK2, a protein kinase often overexpressed in a variety of cancer cell types, appears to be correlated with malignant transformation, tumor growth and survival. CK2 regulates a diverse array of pro-survival cellular processes including epidermal growth factor receptor (EGFR) signaling, PI3K/AKT/mTOR signaling, hedgehog (Hh) signaling, Hsp90 machinery, hypoxia, and interleukin (IL)-6 expression. CK2 also regulates the activity of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair. CK2 is upregulated by SARS-COV-2 and is associated with SARS-COV-2 viral replication and the development of cytokine storm.

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Silmitasertib (CX-4945) Sodium is a potent, selective, orally bioavailable inhibitor of protein kinase CK2 (casein kinase 2), a serine/threonine kinase involved in cell survival, proliferation, and angiogenesis [1][2][3][4]
CK2 is overexpressed in various human cancers, and its activity promotes tumorigenesis by phosphorylating multiple prosurvival and anti-apoptotic substrates [1][4]
The drug exerts antitumor effects by inhibiting CK2-mediated phosphorylation of downstream targets (eIF2α, Akt, STAT3, β-catenin), leading to reduced cell proliferation, induction of apoptosis, and inhibition of angiogenesis [1][2][3][4]
Silmitasertib (CX-4945) Sodium exhibits synergistic cytotoxicity with other anticancer agents, including proteasome inhibitors (PS-341), in hematological malignancies [3][4]
It is being investigated for the treatment of various solid tumors and hematological malignancies, particularly those with high CK2 expression [1][4]

C19H11CLN3O2NA

371.75

371.044

1309357-15-0

Silmitasertib;1009820-21-6

49788959

Light yellow to yellow solid powder

3.616

77.94

1

5

3

26

497

0

ODDAAPQSODILSN-UHFFFAOYSA-M

InChI=1S/C19H12ClN3O2.Na/c20-12-2-1-3-13(9-12)22-18-15-6-7-21-10-16(15)14-5-4-11(19(24)25)8-17(14)23-18;/h1-10H,(H,22,23)(H,24,25);/q;+1/p-1

Sodium 5-[(3-Chlorophenyl)amino]-benzo[c]-2,6-naphthyridine-8-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.60 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 25 mg/mL (67.25 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。