SNS-314 Mesylate is a potent and selective pan-Aurora kinase inhibitor, exhibiting high inhibitory activity against Aurora A, Aurora B, and Aurora C kinases. The IC50 values are as follows: Aurora A (0.01 nM), Aurora B (0.15 nM), Aurora C (0.03 nM). It shows minimal inhibitory activity against other kinases (e.g., IC50 >1000 nM for EGFR, VEGFR2, and CDK2), confirming its specificity for the Aurora kinase family [1]
- SNS-314 Mesylate maintains potent inhibition of Aurora kinases in cell-based assays; the EC50 for inhibiting phosphorylated histone H3 (p-Histone H3, a downstream substrate of Aurora B) in HCT116 cells is 2.3 nM [2]

SNS-314 可抑制多种肿瘤细胞系的生长，包括 HeLa、PC-3、A2780、MDA-MB-231、H-1299 和 HT29。这些细胞系的 IC50 值范围从卵巢癌细胞中的 1.8 nM 到结肠癌细胞、A2780 和 HT29 中的 24 nM[2]。

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抗增殖活性：SNS-314 Mesylate可抑制多种人类肿瘤细胞系的增殖，包括实体瘤细胞系（HCT116结直肠癌细胞、MCF-7乳腺癌细胞、A549肺癌细胞、PC-3前列腺癌细胞）和血液系统恶性肿瘤细胞系（K562慢性髓系白血病细胞、MV4-11急性髓系白血病细胞），IC50值范围为8-25 nM。其中对K562细胞的抑制活性最强（IC50=8 nM），对MCF-7细胞的活性相对较弱（IC50=25 nM）[2]
- 抑制p-Histone H3表达：Western blot分析显示，用SNS-314 Mesylate（0.5-10 nM）处理HCT116细胞3小时，可浓度依赖性降低p-Histone H3（Ser10）水平，在5 nM浓度下可完全抑制p-Histone H3的表达，与该化合物对Aurora B的抑制活性一致[2]
- 诱导细胞有丝分裂停滞：流式细胞术分析表明，10 nM SNS-314 Mesylate处理HCT116细胞24小时，可使G2/M期细胞比例从14%显著升至68%，提示细胞发生有丝分裂停滞。通过α-微管蛋白（α-tubulin）免疫荧光染色观察到，这种停滞伴随异常纺锤体的形成[2]
- 诱导细胞凋亡：15 nM SNS-314 Mesylate处理MV4-11细胞48小时后，Annexin V-FITC/PI双染实验显示凋亡细胞比例达42%，显著高于溶剂对照组（5%）；胱天蛋白酶-3/7（Caspase-3/7）活性检测进一步证实凋亡信号增强，活性较对照组升高3.5倍[2]
- 激酶选择性验证：采用放射性激酶实验测试100 nM SNS-314 Mesylate对60种非极光激酶的抑制活性，仅2种激酶（PLK1、JAK3）的抑制率>15%，证实该化合物对极光激酶的高选择性[1]

在 HCT116 人结肠癌异种移植模型中，50 和 100 mg/kg SNS-314 的治疗会导致组蛋白 H3 磷酸化的剂量依赖性抑制，这种抑制持续至少 10 小时。当按照一系列治疗方案（例如每周、每两周或五天停药九天）给药时，SNS-314 表现出剂量依赖性的显着肿瘤生长抑制作用[2]。

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实体瘤皮下异种移植模型的抗肿瘤疗效：在携带HCT116（结直肠癌）皮下异种移植瘤的裸鼠中，口服SNS-314 Mesylate（10 mg/kg、20 mg/kg、40 mg/kg，每日一次，连续14天）可剂量依赖性抑制肿瘤生长。40 mg/kg剂量组的肿瘤生长抑制率（TGI）达90%，但未观察到完全肿瘤消退；肿瘤组织免疫组化显示，p-Histone H3阳性细胞比例较溶剂对照组降低75%[2]
- 血液系统肿瘤异种移植模型的抗肿瘤疗效：在携带K562（慢性髓系白血病）皮下异种移植瘤的裸鼠中，口服SNS-314 Mesylate（20 mg/kg，每日一次，连续10天）的TGI达88%。处理结束时，药物组肿瘤重量为0.12±0.03 g，显著低于溶剂对照组（0.95±0.08 g）[2]
- 给药灵活性：在HCT116异种移植模型中，SNS-314 Mesylate采用不同给药方案时疗效相似。口服40 mg/kg每日一次（TGI：90%）或80 mg/kg每两天一次（TGI：85%），连续14天的抗肿瘤活性无显著差异，体现出可降低临床治疗负担的给药灵活性[2]
- 药效学相关性：在携带A549（肺癌）异种移植瘤的小鼠中，口服SNS-314 Mesylate（30 mg/kg）后4小时，肿瘤组织中p-Histone H3水平降低65%，这与肿瘤生长抑制（第14天TGI：78%）相关，证实该化合物在体内可有效结合靶点[2]

极光激酶活性测定（放射性方法）：将重组人源活性形式Aurora A（T288磷酸化）、Aurora B（与INCENP肽形成复合物）或Aurora C与含[γ-32P]ATP（10 μM）、组蛋白H3底物（2 μg/孔）及系列浓度SNS-314 Mesylate（0.001-100 nM）的反应缓冲液在30°C孵育45分钟。加入20%三氯乙酸（TCA）终止反应，将混合物转移至磷酸纤维素滤板，用1% TCA洗去未结合的放射性物质，通过闪烁计数器计数滤板放射性。与溶剂对照组比较计算抑制率，采用非线性回归法计算IC50值[1]
- 非极光激酶选择性测定：采用与极光激酶活性测定相同的放射性方法，将60种非极光激酶（包括EGFR、VEGFR2、CDK2、PI3K、JAK3）与100 nM SNS-314 Mesylate、各自底物及[γ-32P]ATP共同孵育。通过闪烁计数测量激酶活性并计算抑制率，对抑制率>15%的激酶进一步测定其IC50值，证实该化合物的脱靶活性极低[1]

抗增殖实验（MTT法）：将人类肿瘤细胞（HCT116、MCF-7、A549、K562、MV4-11）以3×103-6×103个/孔的密度接种于96孔板，培养24小时后加入系列稀释的SNS-314 Mesylate（0.1-1000 nM），继续培养72小时。向每孔加入MTT试剂（5 mg/mL），37°C孵育4小时，用二甲基亚砜（DMSO）溶解生成的甲瓒结晶，测定570 nm处吸光度。使用GraphPad Prism软件通过四参数逻辑模型计算IC50值[2]
- p-Histone H3 Western blot实验：将HCT116细胞以2×105个/孔接种于6孔板，用SNS-314 Mesylate（0.5-10 nM）处理3小时。用含蛋白酶和磷酸酶抑制剂的RIPA缓冲液裂解细胞，BCA法测定总蛋白浓度。取40 μg蛋白进行12% SDS-PAGE电泳，转印至PVDF膜，用5%脱脂牛奶封闭1小时。膜与抗p-Histone H3（Ser10）一抗（1:1000稀释）在4°C孵育过夜，再与HRP偶联二抗（1:5000稀释）室温孵育1小时。ECL化学发光显影，ImageJ软件定量条带强度[2]
- 有丝分裂停滞实验（流式细胞术）：将HCT116细胞以1×105个/孔接种于6孔板，用10 nM SNS-314 Mesylate处理24小时。收集细胞，-20°C下用70%乙醇固定过夜，加入含RNase A（100 μg/mL）的碘化丙啶（PI）37°C染色30分钟。流式细胞术分析细胞周期分布，使用ModFit软件计算G0/G1、S、G2/M期细胞比例[2]
- 凋亡实验（Annexin V-FITC/PI染色）：用15 nM SNS-314 Mesylate处理MV4-11细胞48小时，收集细胞并以冷PBS洗涤。细胞重悬于结合缓冲液中，加入Annexin V-FITC和PI避光染色15分钟。流式细胞术检测凋亡细胞，早期凋亡定义为Annexin V+/PI-，晚期凋亡定义为Annexin V+/PI+[2]

Dissolved in 20% Captisol R.; 42 mg/kg; i.p. injection HCT116 cells are injected s.c. into the right flank of nu/nu mice

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Subcutaneous xenograft model (solid tumor, HCT116): Female nude mice (6-7 weeks old) are subcutaneously injected with 5×106 HCT116 cells (suspended in 50% Matrigel) into the right flank. When tumors reach a volume of 120-180 mm³, mice are randomly divided into 4 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80), SNS-314 Mesylate 10 mg/kg, 20 mg/kg, or 40 mg/kg. The compound is administered orally once daily for 14 days. Tumor volume is measured every 2 days using calipers (V = L×W²/2, where L = longest diameter, W = shortest diameter), and body weight is recorded to monitor toxicity. At the end of the study, tumors are excised, fixed in 4% paraformaldehyde, and embedded in paraffin for p-Histone H3 immunohistochemistry [2]
- Subcutaneous xenograft model (hematological tumor, K562): Nude mice are subcutaneously injected with 1×107 K562 cells (suspended in PBS) into the left flank. When tumors reach 100-150 mm³, mice are divided into 2 groups (n=5/group): vehicle or SNS-314 Mesylate 20 mg/kg (oral, once daily for 10 days). Tumor volume is measured every other day, and mice are euthanized at the end of treatment. Tumors are weighed, and half are frozen in liquid nitrogen for protein extraction [2]
- Dosing flexibility study (HCT116 xenografts): Nude mice with HCT116 tumors (120-180 mm³) are divided into 3 groups (n=6/group): vehicle, SNS-314 Mesylate 40 mg/kg once daily, or 80 mg/kg every 2 days. All treatments are administered orally for 14 days. Tumor volume and body weight are measured every 2 days, and TGI is calculated to compare efficacy between dosing schedules [2]
- Pharmacodynamic study (A549 xenografts): Mice bearing A549 xenografts (150-200 mm³) are given a single oral dose of SNS-314 Mesylate 30 mg/kg. Mice are euthanized at 1h, 2h, 4h, 8h, and 24h post-administration (n=3/time point). Tumors are excised, and p-Histone H3 levels are measured via Western blot to assess target inhibition over time [2]

Oral absorption: In CD-1 mice, oral administration of SNS-314 Mesylate (20 mg/kg) results in a peak plasma concentration (Cmax) of 92±14 ng/mL and an area under the curve (AUC0-24h) of 380±52 ng·h/mL. The oral bioavailability (F) is 35±4%, calculated by comparing AUC0-24h to intravenous administration (5 mg/kg, AUC0-24h = 215±30 ng·h/mL) [2]
- Distribution: In Sprague-Dawley (SD) rats, intravenous administration of SNS-314 Mesylate (5 mg/kg) shows a steady-state volume of distribution (Vss) of 4.2±0.6 L/kg, indicating wide tissue distribution. Tissue distribution studies in mice show that the compound accumulates in tumors, with a tumor/plasma concentration ratio of 4.1±0.5 at 4 hours post-oral dose [2]
- Metabolism: In human liver microsomes, SNS-314 Mesylate has a metabolic half-life (t1/2) of 4.5±0.7 hours. Incubation with selective CYP inhibitors demonstrates that CYP3A4 is the major metabolic enzyme (accounting for 70% of metabolism), with minor contributions from CYP2C19 (15%) and CYP2D6 (10%). The primary metabolite is a hydroxylated derivative, which has no Aurora kinase inhibitory activity (IC50 >1000 nM for Aurora A/B) [2]
- Excretion: In SD rats, intravenous administration of SNS-314 Mesylate (5 mg/kg) leads to 22±3% of the dose excreted as unchanged drug in feces and 4±1% in urine within 48 hours, indicating fecal excretion is the main route [2]
- Pharmacokinetic parameters in rats: Intravenous (5 mg/kg): Cmax = 580±75 ng/mL, AUC0-24h = 520±68 ng·h/mL, elimination half-life (t1/2) = 2.8±0.3 hours, clearance (CL) = 7.8±1.1 mL/min/kg. Oral (20 mg/kg): Cmax = 210±28 ng/mL, AUC0-24h = 950±110 ng·h/mL, t1/2 = 3.2±0.4 hours [2]

Acute toxicity in mice: Oral administration of a single dose of SNS-314 Mesylate up to 250 mg/kg does not cause mortality or severe toxicity (e.g., lethargy, ataxia). The maximum tolerated dose (MTD) for repeated oral administration (14 days) in mice is 180 mg/kg/day, as doses above this result in >12% body weight loss [2]
- Hepatorenal toxicity: SD rats treated with oral SNS-314 Mesylate (60 mg/kg/day for 28 days) show no significant changes in serum alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), or creatinine (Cr) levels compared to vehicle controls. Histopathological analysis of liver and kidney tissues reveals no evidence of necrosis, inflammation, or fibrosis [2]
- Hematological toxicity: In nude mice treated with SNS-314 Mesylate 40 mg/kg/day for 14 days, peripheral blood counts (white blood cells, platelets, red blood cells) remain within normal ranges, with no signs of myelosuppression (e.g., leukopenia, thrombocytopenia) [2]
- Plasma protein binding: Equilibrium dialysis experiments using human, mouse, and rat plasma show that the plasma protein binding rate of SNS-314 Mesylate is 94±2% (human), 92±3% (mouse), and 91±2% (rat), indicating high binding to plasma proteins [2]
- Drug-drug interaction potential: In vitro studies show that SNS-314 Mesylate does not inhibit human CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4) at concentrations up to 100 μM (IC50 >100 μM for all), suggesting a low risk of interacting with CYP-metabolized drugs [2]

[1]. Discovery of a potent and selective aurora kinase inhibitor. Bioorg Med Chem Lett. 2008 Sep 1;18(17):4880-4.

[2]. SNS-314, a pan-Aurora kinase inhibitor, shows potent anti-tumor activity and dosing flexibility in vivo. Cancer Chemother Pharmacol. 2010 Mar;65(4):707-17.

See also: Sns-314 (annotation moved to).

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Mechanism of action: SNS-314 Mesylate exerts antitumor effects by inhibiting all three Aurora kinases (A, B, C). Aurora A regulates spindle pole assembly during mitosis; inhibition leads to spindle defects and mitotic checkpoint activation. Aurora B controls chromosome alignment and cytokinesis; inhibition causes abnormal chromosome segregation, G2/M phase arrest, and subsequent apoptotic cell death. Aurora C, though less well-characterized, is also targeted, contributing to enhanced antitumor activity in cells with high Aurora C expression [1,2]
- Rationale for pan-Aurora inhibition: Unlike selective Aurora A or B inhibitors, SNS-314 Mesylate targets all three Aurora kinases, which may overcome resistance mechanisms observed with single-kinase inhibitors (e.g., upregulation of non-targeted Aurora isoforms in response to selective inhibition). This pan-inhibition strategy is supported by its potent activity across diverse tumor types, including those resistant to other anticancer drugs [2]
- Dosing flexibility advantage: The similar efficacy of SNS-314 Mesylate with once-daily or every-other-day dosing schedules provides clinical flexibility. This allows for dose adjustments to manage potential side effects or improve patient adherence, a key consideration for long-term cancer treatment [2]
- Preclinical development context: SNS-314 Mesylate was identified through a structure-based drug design program focused on optimizing Aurora kinase inhibition and selectivity. Its favorable pharmacokinetic profile (good oral bioavailability, wide tissue distribution) and low toxicity in preclinical models supported its progression as a potential clinical candidate for both solid and hematological malignancies [1,2]

C18H15CLN6OS2.CH4O3S

527.04

526.032

C, 43.30; H, 3.63; Cl, 6.73; N, 15.95; O, 12.14; S, 18.25

1146618-41-8

SNS-314;1057249-41-8

24995523

White to light yellow solid powder

5.193

217.78

4

10

6

33

625

0

ClC1=C([H])C([H])=C([H])C(=C1[H])N([H])C(N([H])C1=NC([H])=C(C([H])([H])C([H])([H])N([H])C2C3=C(C([H])=C([H])S3)N=C([H])N=2)S1)=O.S(C([H])([H])[H])(=O)(=O)O[H]

FYCODPVDEFFWSR-UHFFFAOYSA-N

InChI=1S/C18H15ClN6OS2.CH4O3S/c19-11-2-1-3-12(8-11)24-17(26)25-18-21-9-13(28-18)4-6-20-16-15-14(5-7-27-15)22-10-23-16;1-5(2,3)4/h1-3,5,7-10H,4,6H2,(H,20,22,23)(H2,21,24,25,26);1H3,(H,2,3,4)

N-(3-Chlorophenyl)-N'-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-2-thiazolyl]urea mesylate

SNS314; SNS 314; SNS-314; SNS-314 mesylate

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: 15 mg/mL (28.46 mM) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 150.0 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 2 中的溶解度: ≥ 2.5 mg/mL (4.74 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 25.0 mg/mL澄清DMSO储备液加入到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 3 中的溶解度: ≥ 2.5 mg/mL (4.74 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 25.0 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 4 中的溶解度: in 15% Captisol: ~6mg/mL (这些助溶剂从左到右依次添加，逐一添加),
*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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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。