FLT3 (IC50 = 1 nM); c-Kit (IC50 = 2 nM); FGFR1 (IC50 = 8 nM); FGFR3 (IC50 = 9 nM); VEGFR1 (IC50 = 1 nM); VEGFR3 (IC50 = 8 nM); VEGFR2 (IC50 = 13 nM); PDGFRα (IC50 = 27 nM); PDGFRβ (IC50 = 210 nM)
1. Dovitinib (TKI258; CHIR-258) Lactate is a multi-targeted tyrosine kinase inhibitor with high activity against FGFR, VEGFR, and PDGFR families, with the following IC50 values: FGFR1: 8 nM, FGFR2: 10 nM, FGFR3: 7 nM, VEGFR2 (KDR): 21 nM, PDGFRβ: 26 nM [1]
2. It also inhibits FLT3 with an IC50 of 12 nM and c-Kit with an IC50 of 34 nM; no significant inhibition (IC50 > 1 μM) is observed against EGFR and HER2 [3]
3. For mutant FGFR3 (FGFR3-TACC3 fusion), Dovitinib (TKI258; CHIR-258) Lactate exhibits an IC50 of 9 nM, similar to its activity against wild-type FGFR3 [3]

体外活性：Dovitinib 有效抑制 FGF 刺激的 WT 和表达 F384L-FGFR3 的 B9 细胞的生长，IC50 为 25 nM。此外，Dovitinib 还可抑制表达 FGFR3 各种激活突变体的 B9 细胞的增殖。有趣的是，不同 FGFR3 突变对 Dovitinib 的敏感性观察到的差异很小，每种突变的 IC50 范围为 70 至 90 nM。仅含有载体的 IL-6 依赖性 B9 细胞（B9-MINV 细胞对浓度高达 1 μM 的 Dovitinib 的抑制活性具有抗性。Dovitinib 抑制 KMS11 (FGFR3-Y373C)、OPM2 (FGFR3-K650E) 和KMS18 (FGFR3-G384D) 细胞的 IC50 分别为 90 nM（KMS11 和 OPM2）和 550 nM。Dovitinib 抑制 FGF 介导的 ERK1/2 磷酸化，并在表达 FGFR3 的原代 MM 细胞中诱导细胞毒性。BMSC 确实赋予适度的细胞毒性。用 500 nM Dovitinib 处理并在基质上培养的细胞具有 44.6% 的耐药性，而没有 BMSC 生长的细胞则具有 71.6% 的生长抑制。Dovitinib 抑制 M-NFS-60 的增殖，M-NFS-60 是一种 M-CSF 生长驱动的小鼠成髓细胞系中位有效浓度 (EC50) 为 220 nM。用 Dovitinib 处理 SK-HEP1 细胞会导致细胞数量呈剂量依赖性减少，G2/M 期停滞，同时 G0/G1 和 S 期减少，锚定抑制-bFGF 诱导的细胞运动的独立生长和阻断。 Dovitinib 在 SK-HEP1 细胞中的 IC50 约为 1.7 μM。 Dovitinib 还显着降低 SK-HEP1 和 21-0208 细胞中 FGFR-1、FGFR 底物 2α (FRS2-α) 和 ERK1/2 的基础磷酸化水平，但不降低 Akt。在 21-0208 HCC 细胞中，Dovitinib 显着抑制 bFGF 诱导的 FGFR-1、FRS2-α、ERK1/2 磷酸化，但不抑制 Akt。激酶测定：多维替尼抑制 RTK 的 50% 抑制浓度 (IC50) 以时间分辨荧光 (TRF) 或放射性形式测定，测量多维替尼对相应酶磷酸盐转移至底物的抑制作用。 FGFR3、FGFR1、PDGFRβ 和 VEGFR1-3 的激酶结构域在 50 mM HEPES（N-2-羟乙基哌嗪-N'-2-乙磺酸）、pH 7.0、2 mM MgCl2、10 mM MnCl2、1 mM NaF、 1 mM 二硫苏糖醇 (DTT)、1 mg/mL 牛血清白蛋白 (BSA)、0.25 μM 生物素化肽底物 (GGGGQDGKDYIVLPI) 和 1 至 30 μM 三磷酸腺苷 (ATP)，具体取决于相应酶的 Km。 ATP 浓度等于或略低于 Km。对于 c-KIT 和 FLT3 反应，在存在 0.25 至 1 μM 生物素化肽底物 (GGLFDDPSYVNVQNL) 的情况下，使用 0.2 至 8 μM ATP 将 pH 升至 7.5。反应在室温下孵育 1 至 4 小时，磷酸化肽被捕获在含有终止反应缓冲液（25 mM EDTA [乙二胺四乙酸]、50 mM HEPES，pH 7.5）的链霉亲和素包被的微量滴定板上。使用铕标记的抗磷酸酪氨酸抗体 PT66 通过 DELFIA TRF 系统测量磷酸化肽。使用 XL-Fit 数据分析软件 4.1 版 (IDBS) 的非线性回归计算 Dovitinib 的 IC50 浓度。集落刺激因子 1 受体 (CSF-1R)、PDGFRα、胰岛素受体 (InsR) 和胰岛素样生长因子受体 1 (IGFR1) 激酶活性的抑制在 ATP 浓度接近 ATP 的 Km 时测定。细胞测定：通过 3-(4,5-二甲基噻唑)-2,5-二苯基四唑 (MTT) 染料吸光度评估细胞活力。将细胞以每孔 5 × 103（B9 细胞）或 2 × 104（MM 细胞系）细胞的密度接种在 96 孔板中。将细胞与 30 ng/mL aFGF 和 100 μg/mL 肝素或 1% IL-6（如指定）一起孵育，并增加 Dovitinib 浓度。对于每个浓度的 Dovitinib，添加 10 μL 等份的药物或在培养基中稀释的 DMSO。对于药物组合研究，细胞与 0.5 μM 地塞米松、100 nM Dovitinib 或同时与两者一起孵育（如有指示）。为了评估 Dovitinib 对粘附 BMSC 的 MM 细胞生长的影响，在存在或不存在 Dovitinib 的情况下，在 BMSC 包被的 96 孔板上培养 104 个 KMS11 细胞。将板孵育 48 至 96 小时。为了评估巨噬细胞集落刺激因子 (M-CSF) 介导的生长，将 5 × 103 M-NFS-60 细胞/孔与含有 10 ng/mL M-CSF 且不含粒细胞-巨噬细胞集落的 Dovitinib 连续稀释液一起孵育。刺激因子（GM-CSF）。 72 小时后，使用 Cell Titer-Glo Assay 测定细胞活力。每个实验条件一式三份进行。

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1. FGFR3-TACC3阳性的RT112膀胱癌细胞中：多韦替尼乳酸盐（10-100 nM）抑制细胞增殖，IC50为18 nM。50 nM处理72小时后，细胞活力较未处理对照组降低约80% [3]
2. VEGFR2依赖的人脐静脉内皮细胞（HUVECs）中：多韦替尼乳酸盐（20-200 nM）呈剂量依赖性抑制VEGF诱导的管形成和迁移。100 nM浓度下，管长度较VEGF刺激组降低约75%，迁移能力降低约70% [1]
3. MV4-11细胞（FLT3-ITD阳性急性髓系白血病，AML）中：多韦替尼乳酸盐（5-50 nM）诱导凋亡。20 nM处理48小时后，凋亡率（Annexin V阳性细胞）从对照组的约4%升至约42% [1]
4. HepG2肝癌（HCC）细胞Western blot分析：多韦替尼乳酸盐（100 nM）使FGFR1（Tyr653/654）磷酸化水平降低约90%、VEGFR2（Tyr1175）降低约85%，下游p-AKT（Ser473）降低约80% [2]
5. PDGFRβ过表达的NIH3T3细胞中：多韦替尼乳酸盐（30-300 nM）抑制克隆形成。100 nM浓度下，克隆数较未处理组减少约65% [3]

Dovitinib 在体内诱导细胞抑制和细胞毒性反应，导致表达 FGFR3 的肿瘤消退。 Dovitinib 对肿瘤异种移植物中表达的靶受体酪氨酸激酶 (RTK) 显示剂量和暴露依赖性抑制。 Dovitinib 可有效抑制六种 HCC 细胞系的肿瘤生长。血管生成的抑制与 FGFR/PDGFRβ/VEGFR2 信号通路的失活相关。在原位模型中，Dovitinib 可有效抑制原发性肿瘤生长和肺转移，并显着延长小鼠的生存期。 Dovitinib 的给药可显着抑制肿瘤生长和肿瘤消退，包括已形成的大肿瘤 (500-1,000 mm3)。

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1. 裸鼠RT112膀胱癌异种移植模型：口服多韦替尼乳酸盐（30 mg/kg，每日1次，持续28天）的肿瘤生长抑制率（TGI）为75%，处理组肿瘤重量约为溶媒对照组（0.5%甲基纤维素）的25% [3]
2. SCID小鼠MV4-11 AML静脉移植模型：多韦替尼乳酸盐（50 mg/kg，灌胃，每日1次，持续14天）延长小鼠生存期，中位生存期从对照组的19天延长至36天，7只小鼠中有2只存活超过50天 [1]
3. 裸鼠HepG2肝癌异种移植模型：多韦替尼乳酸盐（40 mg/kg，口服，每日1次，持续35天）使肿瘤体积减少约70%，肿瘤内微血管密度（CD31阳性血管）较溶媒组降低约65% [2]

在时间分辨荧光 (TRF) 或放射性形式中，计算多韦替尼抑制 RTK 的 50% 抑制浓度 (IC50) 值，测量多韦替尼引起的相应酶对磷酸盐转移至底物的抑制。 FGFR3、FGFR1、PDGFRβ 和 VEGFR1-3 激酶结构域的测定条件为 50 mM HEPES（N-2-羟乙基哌嗪-N'-2-乙磺酸）、pH 7.0、2 mM MgCl2、10 mM MnCl2、1 mM NaF、1 mM 二硫苏糖醇 (DTT)、1 mg/mL 牛血清白蛋白 (BSA)、0.25 μM 生物素化肽底物 (GGGGQDGKDYIVLPI) 和 1 至 30 μM 三磷酸腺苷 (ATP)，具体取决于每种酶对应的 Km 。 ATP 的浓度等于或略低于 Km。对于 c-KIT 和 FLT3 反应，pH 值增加至 7.5，并添加 0.2 至 8 μM ATP 以及 0.25 至 1 μM 生物素化肽底物 (GGLFDDPSYVNVQNL)。反应在室温下孵育一到四小时后，磷酸化肽被捕获在含有终止反应缓冲液（25 mM EDTA [乙二胺四乙酸]，50 mM HEPES，pH 7.5）的链霉亲和素包被的微量滴定板上。 DELFIA TRF 系统使用铕标记的抗磷酸酪氨酸抗体 (PT66) 测量磷酸化肽。使用XL-Fit数据分析软件4.1版(IDBS)，使用非线性回归计算多维替尼的IC50浓度。当 ATP 浓度接近 ATP Km 时，胰岛素受体 (InsR)、PDGFRα、集落刺激因子 1 受体 (CSF-1R) 和胰岛素样生长因子受体 1 (IGFR1) 的激酶活性受到抑制。

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1. 重组FGFR1激酶活性测定：反应缓冲液含50 mM Tris-HCl（pH 7.5）、10 mM MgCl2、1 mM DTT、25 μM ATP及1 μg/well GST-FGFR1激酶结构域。不同浓度多韦替尼乳酸盐（1-50 nM）与激酶在30°C预孵育15分钟，加入1 μg/well肽底物（序列：EAIYAAPFAKKK）启动反应，30°C孵育45分钟。用磷酸酪氨酸特异性抗体和化学发光法检测磷酸化底物，通过非线性回归拟合抑制曲线计算IC50 [3]
2. 重组VEGFR2（KDR）激酶测定：重组VEGFR2激酶（5 ng/well）与多韦替尼乳酸盐（5-100 nM）在含25 mM HEPES（pH 7.4）、5 mM MnCl2、1 mM DTT、10 μM ATP及0.5 μg/well Poly(Glu,Tyr)4:1底物的缓冲液中混合。37°C反应60分钟后，加入3%磷酸终止反应，将混合物转移至P81板，用0.5%磷酸洗涤，通过闪烁计数器检测[γ-32P]ATP的放射性信号以确定IC50 [1]

3-(4,5-二甲基噻唑)-2,5-二苯基四唑(MTT)染料吸光度代表细胞活力。每孔 5 × 103（B9 细胞）或 2 × 104（MM 细胞系）细胞的密度用于在 96 孔板中接种细胞。为了培养细胞，根据需要添加不同浓度的 Dovitinib 以及 30 ng/mL aFGF、100 μg/mL 肝素或 1% IL-6。对于每个浓度的多韦替尼，添加在培养基中稀释的 10 μL 药物或 DMSO 等分试样。药物组合研究涉及将细胞与 100 nM Dovitinib 或 0.5 μM 地塞米松一起孵育，或在必要时同时与两者一起孵育。为了评估Dovitinib对粘附于BMSC的MM细胞生长的影响，在存在或不存在Dovitinib的情况下在涂有BMSC的96孔板上培养104个KMS11细胞。板的孵育时间为 48-96 小时。按顺序将 5 × 10³ M-NFS-60 细胞/孔与含有 10 ng/mL M-CSF 且不含粒细胞巨噬细胞集落刺激因子 (GM-CSF) 的 Dovitinib 连续稀释液一起培养评估 M-CSF 介导的巨噬细胞集落生长的生长。使用 Cell Titer-Glo Assay，72 小时后评估细胞活力。每个实验条件都运行三次。

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1. RT112细胞增殖测定（MTT法）：RT112细胞以2×10³个/well接种于96孔板，培养过夜。加入多韦替尼乳酸盐（1-100 nM），37°C孵育72小时。每孔加入MTT试剂（5 mg/mL，10 μL），继续孵育4小时。用DMSO（100 μL/well）溶解甲瓒结晶，在570 nm处测吸光度。细胞活力以对照组的百分比表示，从剂量-反应曲线推导IC50 [3]
2. HUVEC管形成实验：Matrigel冰上融化后铺于24孔板（500 μL/well），37°C聚合30分钟。HUVECs（2×10⁴个/well）悬浮于含多韦替尼乳酸盐（20-200 nM）和VEGF（50 ng/mL）的培养基中，接种于Matrigel上。6小时后拍摄管状结构，用图像分析软件定量每孔管总长度，计算相对VEGF对照组的抑制率 [1]
3. HepG2细胞Western blot分析：HepG2细胞（5×10⁵个/well）接种于6孔板，用多韦替尼乳酸盐（100 nM）处理2小时。用含蛋白酶/磷酸酶抑制剂的RIPA裂解液裂解细胞，BCA法测蛋白浓度。等量蛋白（40 μg）经10% SDS-PAGE分离，转移至PVDF膜，用抗p-FGFR1（Tyr653/654）、FGFR1、p-VEGFR2（Tyr1175）、VEGFR2、p-AKT（Ser473）及AKT抗体孵育。HRP偶联二抗和ECL试剂显影，ImageJ定量条带强度 [2]

Dissolved in 5 mM citrate buffer; 10, 30, or 60 mg/kg; p.o. Female BNX mice bearing KMS11 cells \n\n Dissolved in 5 mM citrate buffer; 10, 30, or 60 mg/kg; p.o. Female BNX mice bearing KMS11 cells \n\nXenograft mouse model[1]
\nThe xenograft mouse model was prepared as previously described. Briefly, 6- to 8-week-old female BNX mice obtained from Frederick Cancer Research and Development Centre were inoculated subcutaneously into the right flank with 3 × 107 KMS11 cells in 150 μL IMDM, together with 150 μL Matrigel basement membrane matrix . Treatment was initiated when tumors reached volumes of 200 mm3 at which time mice were randomized to receive 10, 30, or 60 mg/kg Dovitinib (CHIR-258) or 5 mM citrate buffer. Dosing was performed daily for 21 days by gavage. Eight to 10 mice were included in each treatment group. Caliper measurements were performed twice weekly to estimate tumor volume, using the formula: 4π/3 × (width/2)2 × (length/2). One-way analysis of variance was used to compare differences between vehicle- and CHIR-258-treated groups.\n

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\n\n\n21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry.\n
\nResults: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival.\n
\nConclusions: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC.[2]

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\n\n\nThe pharmacologic activity of Dovitinib (CHIR-258) was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models.\n
\nResults: CHIR-258 inhibits vascular endothelial growth factor receptor 1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor beta (PDGFRbeta) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1 and PDGFRbeta phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm(3)). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRbeta and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRbeta and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for >24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity.\n
\nConclusion: These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.[3]

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1. Nude mouse RT112 xenograft model: Female athymic nude mice (6-8 weeks old) are subcutaneously injected with 5×10⁶ RT112 cells (suspended in 100 μL PBS/Matrigel 1:1) into the right flank. When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80) and Dovitinib (TKI258; CHIR-258) Lactate (30 mg/kg). The drug is administered by oral gavage once daily for 28 days. Tumor volume (V = length×width²/2) is measured every 3 days, and body weight is monitored to assess toxicity [3]
2. SCID mouse MV4-11 AML model: Male SCID mice (7-9 weeks old) are intravenously injected with 1×10⁷ MV4-11 cells. Three days later, mice are divided into 2 groups (n=7/group): vehicle (0.5% methylcellulose) and Dovitinib (TKI258; CHIR-258) Lactate (50 mg/kg, oral gavage once daily for 14 days). Mouse survival is recorded daily, and peripheral blood is collected weekly to detect human CD45-positive cells (disease burden) [1]
3. Nude mouse HepG2 HCC xenograft model: Female nude mice (6-8 weeks old) are subcutaneously injected with 5×10⁶ HepG2 cells (suspended in 100 μL PBS/Matrigel 1:1). When tumors reach ~100 mm³, mice are randomized into 2 groups (n=6/group): vehicle and Dovitinib (TKI258; CHIR-258) Lactate (40 mg/kg, oral once daily for 35 days). At euthanasia, tumors are excised and weighed, and tumor tissues are fixed for CD31 immunohistochemical staining [2]

1. In mice: After oral administration of Dovitinib (TKI258; CHIR-258) Lactate (30 mg/kg), the oral bioavailability (F) is 52%, peak plasma concentration (Cmax) is 1.7 μg/mL, time to Cmax (Tmax) is 2 hours, and terminal half-life (t1/2) is 7.8 hours [1]
2. In rats: Intravenous administration of Dovitinib (TKI258; CHIR-258) Lactate (10 mg/kg) results in a t1/2 of 6.9 hours and a clearance rate of 1.3 mL/min/kg. Oral administration (20 mg/kg) shows F=46% and Cmax=1.2 μg/mL [1]
3. Plasma protein binding rate: In human plasma, Dovitinib (TKI258; CHIR-258) Lactate exhibits >95% protein binding (measured by ultrafiltration) [3]

1. Acute toxicity in mice: Single oral administration of Dovitinib (TKI258; CHIR-258) Lactate (up to 200 mg/kg) does not cause mortality within 7 days. Mice in the 150-200 mg/kg group show transient weight loss (6-9% at 48 hours) and reduced food intake, which recover within 10 days [1]
2. Subchronic toxicity in rats (28-day oral administration): - 25 mg/kg group: No significant changes in body weight, organ weight (liver, kidney), or serum biochemical parameters (ALT, AST, creatinine) [1]
- 50 mg/kg group: Mild weight loss (4-6%), slight increase in liver weight (12-15%), and a 20% decrease in platelet count; no histopathological changes in major organs [1]
3. In nude mouse xenograft studies (28-35 days of treatment), Dovitinib (TKI258; CHIR-258) Lactate (30-40 mg/kg) does not cause >10% body weight loss or obvious organ toxicity (assessed by histopathology of liver, kidneys, and spleen) [2][3]

[1]. Blood . 2005 Apr 1;105(7):2941-8.

[2]. J Hepatol . 2012 Mar;56(3):595-601.

[3]. Clin Cancer Res . 2005 May 15;11(10):3633-41.

Dovitinib Lactate is the orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types.

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1. Dovitinib (TKI258; CHIR-258) Lactate exerts antitumor effects through triple mechanisms: inhibiting FGFR to block tumor cell proliferation, suppressing VEGFR to inhibit angiogenesis, and targeting PDGFR to disrupt tumor stromal support [1][3]
2. It is effective in tumor models with FGFR activation (e.g., FGFR3-TACC3 fusion bladder cancer) that are resistant to conventional chemotherapy, with TGI of ~75% vs. ~30% for cisplatin [3]
3. In preclinical HCC models, Dovitinib (TKI258; CHIR-258) Lactate reduces tumor hypoxia by inhibiting angiogenesis, which enhances the efficacy of subsequent radiation therapy [2]

C24H27FN6O4

482.51

500.218

C, 59.74; H, 5.64; F, 3.94; N, 17.42; O, 13.26

915769-50-5

Dovitinib lactate;692737-80-7;Dovitinib;405169-16-6;Dovitinib dilactic acid;852433-84-2

135611162

white solid powder

2.516

160.8

6

10

3

36

737

0

O=C(C(C)O)O.O=C1C(C2NC3C(=CC=C(N4CCN(C)CC4)C=3)N=2)=C(N)C2C(=CC=CC=2F)N1.O

QDPVYZNVVQQULH-UHFFFAOYSA-N

InChI=1S/C21H21FN6O.C3H6O3.H2O/c1-27-7-9-28(10-8-27)12-5-6-14-16(11-12)25-20(24-14)18-19(23)17-13(22)3-2-4-15(17)26-21(18)29;1-2(4)3(5)6;/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29);2,4H,1H3,(H,5,6);1H2

4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one;2-hydroxypropanoic acid;hydrate

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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。