VEGFR3 (IC50 = 20 nM); Braf (IC50 = 22 nM); Raf-1 (IC50 = 6 nM); VEGFR2 (IC50 = 90 nM); PDGFRβ (IC50 = 57 nM); BrafV599E (IC50 = 38 nM); c-Kit (IC50 = 68 nM); Flt3 (IC50 = 58 nM)

索拉非尼的 IC50 值分别为 22 nM 和 38 nM，抑制野生型和 V599E 突变体 B-Raf 活性。此外，mVEGFR2 (Flk-1) 以及 mVEGFR3、mPDGFRβ、Flt3 和 c-Kit 均被索拉非尼有效抑制，IC50 值分别为 15 nM、20 nM、57 nM、58 nM 和 68 nM。索拉非尼的 IC50 为 580 nM，仅中度抑制 FGFR-1。甲苯磺酸索拉非尼对以下靶标无效：ERK-1、MEK-1、EGFR、HER-2、IGFR-1、c-Met、PKB、PKA、cdk1/cyclinB、PKCα、PKCγ 和 pim-1。在 NIH 3T3 细胞中，索拉非尼显着降低 VEGFR2 磷酸化（IC50 为 30 nM），并显着降低 HEK-293 细胞中 Flt-3 磷酸化（IC50 为 20 nM）。在大多数细胞系中，索拉非尼有效抑制 MEK 1/2 和 ERK 1/2 磷酸化，但在 A549 或 H460 细胞中则不然。它对PKB途径的抑制没有影响。 Sorafenib 的 IC50 分别为 0.28 μM 和 2.6 μM，可防止 HAoSMC 和 MDA-MB-231 细胞增殖。 [1] 除了抑制 RAF/MEK/ERK 信号通路外，索拉非尼还以不依赖于 MEK/ERK 的方式显着抑制 eIF4E 磷酸化并下调肝细胞癌 (HCC) 细胞中的 Mcl-1 水平。索拉非尼的 IC50 值分别为 6.3 μM 和 4.5 μM，抑制 PLC/PRF/5 和 HepG2 细胞的增殖，并显着诱导细胞凋亡。 [2]

口服索拉非尼 (60 mg/kg) 对多种人类肿瘤异种移植模型（包括 MDA-MB-231、Colo-205、HT-29、DLD-1）没有毒性，且具有广谱、剂量依赖性抗肿瘤活性、NCI-H460 和 A549。索拉非尼治疗显着降低 MDA MB-231、HT-29 和 Colo-205 肿瘤异种移植物中的肿瘤微血管面积（MVA）和微血管密度（MVD），这与其抗肿瘤功效相关。然而，它对 HT-29 或 MDA-MB-231 异种移植物中的 MEK 1/2 磷酸化或 pERK 1/2 水平没有影响。 [1]在 SCID 小鼠中，索拉非尼治疗导致 PLC/PRF/5 肿瘤异种移植物的剂量依赖性生长抑制，10 mg/kg 和 30 mg/kg 时的 TGI 分别为 49% 和 78%。这与抑制 ERK 和 eIF4E 磷酸化、减少微血管面积以及诱导肿瘤细胞凋亡相一致。 [2] 通过抑制 NF-B 介导的 Mcl-1 和 cIAP2 表达，索拉非尼以剂量依赖性方式使 bax-/- 细胞对 TRAIL 敏感。在 TRAIL 耐药的 HCT116 bax-/- 和 HT29 肿瘤异种移植物中，索拉非尼 (30-60 mg/kg) 和 TRAIL (5 mg/kg) 显示出显着的疗效。 [3]

将 Raf-1 (80 ng)、wt BRAF (80 ng) 或 V599E BRAF (80 ng) 与 MEK-1 (1 μg) 在测定缓冲液（20 mM Tris (pH 8.2)、100 mM NaCl、5 mM MgCl2 和 0.15% β-巯基乙醇）以测试该化合物对不同 RAF 激酶亚型的影响。添加 25 μL 10 μM γ-[33P]ATP (400 Ci/mol) 并将混合物在 32°C 下孵育 25 分钟，启动 RAF 激酶测定（最终体积为 50 μL）。通过将磷酸化的 MEK-1 过滤到磷酸纤维素垫上，未与蛋白质结合的放射性被去除。然后收获磷酸化的 MEK-1。使用 β 板计数器，在微波加热干燥后测量过滤器结合的放射性。

72 小时内，甲苯磺酸索拉非尼以逐渐升高的浓度注入细胞。 Cell TiterGlo ATP 发光检测试剂盒用于计算细胞数量。该测定通过测量发光信号来计算每个孔中的活细胞数量，该信号取决于细胞 ATP 的量。

Mice: Female NCr-nu/nu mice are used. Mice bearing 75 to 150 mg tumors are treated orally with Sorafenib (7.5 to 60 mg/kg), administered daily for 9 days. In each model, Sorafenib produces dose-dependent tumor growth inhibition with no evidence of toxicity, as measured by increased weight loss relative to control animals or drug-related lethality. In parallel to the antitumor efficacy studies, additional groups of four mice bearing 100 to 200 mg tumors are treated orally with vehicle or Sorafenib (30 to 60 mg/kg), administered daily for 5 days, which is the shortest treatment duration producing complete tumor stasis in the treated groups.
Rats: Male albino rats weighing 100 to 120 g are used for the study. Rats are weighed and randomly split into three groups following an acclimatization period. For 8 weeks, the car is given daily to Group 1 (the healthy control group; n=10). An i.p. single dose of 200 mg/kg DENA is administered to Group 2 (the DENA group; n=15). Six weeks after receiving a DENA intravenously in Group 3 (the Sorafenib group; n=12), Sorafenib is administered orally at a dose of 10 mg/kg daily for two weeks. Rats are weighed, put to sleep with ether, killed at the conclusion of the experiment (8 weeks), and their livers are removed. Fresh liver is weighed after being dried on a clean paper towel and going through two ice-cold saline washes. The liver index is calculated using the formula liver weight (g)/final body weight (g)×100.

[1]. Cancer Res . 2006 Dec 15;66(24):11851-8.

[2]. Cancer Res (2004) 64 (19): 7099–7109.

[3]. Cancer Cell . 2007 Jul;12(1):66-80.

C21H16CLF3N4O3

464.82

464.09

C, 54.26; H, 3.47; Cl, 7.63; F, 12.26; N, 12.05; O, 10.33

284461-73-0

Sorafenib Tosylate;475207-59-1;Sorafenib-d3;1130115-44-4;Sorafenib-d4;1207560-07-3;Sorafenib-13C,d3;1210608-86-8

white solid powder

CNC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F

MLDQJTXFUGDVEO-UHFFFAOYSA-N

InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)

4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide

BAY 43-9006; BAY-439-006; BAY439006; BAY-439006; BAY 439006; BAY 549085; trade name: Nexavar; SFN

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

Solubility in Formulation 1: 4 mg/mL (8.61 mM) in 2% DMSO + 40% PEG300 + 5% Tween80 + 53% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (4.47 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 4: ≥ 2.08 mg/mL (4.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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Solubility in Formulation 5: 5%DMSO+45%PEG400+50%H2O: 0.375mg/mL

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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。