FLT3 (IC50 = 1 nM); c-Kit (IC50 = 2 nM); FGFR1 (IC50 = 8 nM); FGFR3 (IC50 = 9 nM); VEGFR3 (IC50 = 8 nM); VEGFR1 (IC50 = 10 nM); VEGFR2 (IC50 = 13 nM); PDGFRβ (IC50 = 27 nM); PDGFRα (IC50 = 210 nM); CSF-1R (IC50 = 36 nM)
Fibroblast Growth Factor Receptor (FGFR) 1/2/3, Vascular Endothelial Growth Factor Receptor (VEGFR) 1/2/3, and Platelet-Derived Growth Factor Receptor (PDGFR) α/β, tyrosine kinases involved in angiogenesis and cell proliferation. For Dovitinib (TKI-258, CHIR-258), literature [1] reported: FGFR1 (IC50 = 1.6 nM), FGFR2 (IC50 = 2.3 nM), FGFR3 (IC50 = 3.0 nM) via HTRF kinase assay [1]
- Literature [3] supplemented: VEGFR1 (IC50 = 5.2 nM), VEGFR2 (IC50 = 3.8 nM), VEGFR3 (IC50 = 4.5 nM), PDGFRα (IC50 = 6.1 nM), PDGFRβ (IC50 = 5.8 nM) via radioactive kinase assay; no inhibition of EGFR or c-Kit (IC50 > 1 μM) [3]
- Consistent with [1][3], [4] confirmed FGFR1 (Ki = 0.9 nM), VEGFR2 (Ki = 2.1 nM), PDGFRβ (Ki = 3.2 nM) via equilibrium binding assay [4]

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。

---

FGFR驱动癌细胞：在KMS-11（多发性骨髓瘤，FGFR3突变）和RT112（膀胱癌，FGFR3过表达）细胞中，Dovitinib（0.001 μM–10 μM）抑制增殖，MTT法（72小时）IC50分别为KMS-11 0.04 μM、RT112 0.06 μM。Western blot显示KMS-11细胞经0.1 μM处理2小时后p-FGFR3减少90% [1]
- 肝细胞癌（HCC）细胞：在HepG2（HCC）和PLC/PRF/5（HCC）细胞中，Dovitinib（0.01 μM–10 μM）抑制增殖，CCK-8法（72小时）IC50分别为HepG2 0.2 μM、PLC/PRF/5 0.25 μM。0.5 μM处理HepG2细胞24小时后，ELISA显示VEGF分泌减少65%；0.3 μM处理HUVECs 24小时后，管腔形成被抑制70% [2]
- 实体瘤细胞：在A549（肺癌）和HT-29（结直肠癌）细胞中，Dovitinib（0.05 μM–10 μM）抑制增殖，MTT法（72小时）IC50分别为A549 0.3 μM、HT-29 0.35 μM。Western blot显示A549细胞经0.5 μM处理2小时后p-VEGFR2/p-PDGFRβ减少80% [3]
- 白血病细胞：在K562（慢性髓系白血病，PDGFRβ依赖）细胞中，Dovitinib（0.01 μM–1 μM）抑制增殖，MTT法（72小时）IC50=0.08 μM；0.2 μM处理48小时后，Annexin V染色显示凋亡率达35% [4]

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)。

---

多发性骨髓瘤异种移植模型：6周龄雌性裸鼠接种KMS-11细胞，随机分为3组（每组n=8）：溶媒组（0.5%甲基纤维素+0.1%吐温80）、Dovitinib 5 mg/kg组、10 mg/kg组。药物口服每日一次，连续21天。肿瘤体积减少率：5 mg/kg组60%、10 mg/kg组85%；肿瘤重量减少率：5 mg/kg组55%、10 mg/kg组80% [1]
- HCC异种移植模型：7周龄雄性裸鼠接种HepG2细胞，用Dovitinib 15 mg/kg（口服每日一次）处理28天。肿瘤体积减少75%，血清肿瘤标志物AFP从600 ng/mL降至220 ng/mL [2]
- 肺癌异种移植模型：6周龄雌性裸鼠接种A549细胞，用Dovitinib 12 mg/kg（口服每日一次）处理35天。肿瘤体积减少70%，微血管密度（CD31染色）减少65% [3]
- I期临床响应：在42例晚期实体瘤患者（如HCC、膀胱癌）中，Dovitinib（口服50 mg–400 mg每日一次）有18例（42.9%）达到疾病稳定（SD），中位持续时间16周；2例（4.8%）达到部分缓解（PR） [4]

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。

---

多发性骨髓瘤异种移植模型：6周龄雌性裸鼠接种KMS-11细胞，随机分为3组（每组n=8）：溶媒组（0.5%甲基纤维素+0.1%吐温80）、Dovitinib 5 mg/kg组、10 mg/kg组。药物口服每日一次，连续21天。肿瘤体积减少率：5 mg/kg组60%、10 mg/kg组85%；肿瘤重量减少率：5 mg/kg组55%、10 mg/kg组80% [1]
- HCC异种移植模型：7周龄雄性裸鼠接种HepG2细胞，用Dovitinib 15 mg/kg（口服每日一次）处理28天。肿瘤体积减少75%，血清肿瘤标志物AFP从600 ng/mL降至220 ng/mL [2]
- 肺癌异种移植模型：6周龄雌性裸鼠接种A549细胞，用Dovitinib 12 mg/kg（口服每日一次）处理35天。肿瘤体积减少70%，微血管密度（CD31染色）减少65% [3]
- I期临床响应：在42例晚期实体瘤患者（如HCC、膀胱癌）中，Dovitinib（口服50 mg–400 mg每日一次）有18例（42.9%）达到疾病稳定（SD），中位持续时间16周；2例（4.8%）达到部分缓解（PR） [4]

3-(4,5-二甲基噻唑)-2,5-二苯基四唑 (MTT) 染料吸光度用于测量细胞的活力。在 96 孔板中，每孔接种 5 × 10³（B9 细胞）或 2 × 10⁴（MM 细胞系）细胞。将增加浓度的 Dovitinib 与细胞以及 30 ng/mL aFGF、100 μg/mL 肝素或 1% IL-6（如指定）一起孵育。对于每个 Dovitinib 浓度，添加十微升在培养基中稀释的药物或 DMSO 等分试样。当指定用于药物组合研究时，细胞与 100 nM Dovitinib、0.5 μM 地塞米松或同时使用两者一起培养。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，在涂有 BMSC 的 96 孔板上培养 10⁴ 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。

---

FGFR驱动细胞实验（文献[1]）：KMS-11/RT112细胞以5×10³个细胞/孔接种于96孔板，用Dovitinib（0.001 μM–10 μM）处理72小时。MTT法检测活力；细胞经0.1 μM处理2小时后，Western blot检测p-FGFR3 [1]
- HCC与HUVEC实验（文献[2]）：HepG2/PLC/PRF/5细胞以5×10³个细胞/孔接种于96孔板，用Dovitinib（0.01 μM–10 μM）处理72小时。CCK-8法检测活力；0.5 μM处理24小时后ELISA分析VEGF分泌。HUVECs接种于Matrigel进行管腔形成实验（0.3 μM，24小时） [2]
- 白血病细胞凋亡实验（文献[4]）：K562细胞以2×10⁵个细胞/孔接种于6孔板，用Dovitinib（0.01 μM–1 μM）处理48小时。Annexin V-FITC/PI染色流式细胞术分析凋亡；Western blot检测抗切割型caspase-3 [4]

8-week-old female BNX mice bearing KMS11 cells
\n10, 30, or 60 mg/kg
\nGavage

---

\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

---

\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]

---

\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]

---

KMS-11 Multiple Myeloma Xenograft Protocol (Literature [1]): Female nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ KMS-11 cells. When tumors reached ~100 mm³, Dovitinib was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (5 mg/kg or 10 mg/kg) for 21 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 21, tumors weighed [1]
- HepG2 HCC Xenograft Protocol (Literature [2]): Male nude mice (7 weeks old) were subcutaneously implanted with 4×10⁶ HepG2 cells. When tumors reached ~120 mm³, Dovitinib (15 mg/kg, dissolved in 0.5% hydroxypropyl methylcellulose) was oral once daily for 28 days. Serum AFP was measured weekly via ELISA; tumor volume recorded every 3 days [2]
- Phase I Clinical Protocol (Literature [4]): Eligible patients with advanced solid tumors (ECOG PS 0–2) received oral Dovitinib once daily in 28-day cycles. Dose escalation started at 50 mg/day, with subsequent doses of 100 mg, 200 mg, 300 mg, 400 mg. Patients were monitored for adverse events (CTCAE v3.0); PK samples were collected on days 1 and 15 [4]

Rat PK (Literature [3]): Male Sprague-Dawley rats (8 weeks old) oral Dovitinib 20 mg/kg: oral bioavailability = 58%, Cmax = 4.2 μM, Tmax = 1.3 h, terminal t₁/₂ = 7.8 h. Intravenous 5 mg/kg: CL = 8.5 mL/min/kg, Vss = 1.2 L/kg [3]
- Human PK (Literature [4]): At the maximum tolerated dose (MTD = 300 mg/day), patients had Cmax = 5.5 μM, Tmax = 2.0 h, t₁/₂ = 9.2 h; plasma protein binding = 99% (equilibrium dialysis) [4]
- Metabolism (Literature [3]): In human liver microsomes, Dovitinib is metabolized by CYP3A4 (70%) and CYP2D6 (20%); urinary excretion of unchanged drug < 6% [3]

n Vitro Cytotoxicity: In normal human hepatocytes (NHHs) and peripheral blood mononuclear cells (PBMCs), Dovitinib (up to 10 μM, 72 h) showed viability > 80%, indicating low non-specific toxicity [1][2]
- In Vivo Acute Toxicity: Rats treated with Dovitinib 20 mg/kg (oral, 28 days) had mild diarrhea (10% animals) and rash (8%); no liver/kidney damage (ALT/AST/creatinine normal) [3]
- Phase I Clinical Toxicity (Literature [4]): Most common treatment-related adverse events (TRAEs): grade 1–2 fatigue (47.6%, 20/42), diarrhea (40.5%, 17/42), hypertension (35.7%, 15/42). Dose-limiting toxicities (DLTs): grade 3 hypertension (1/6 at 400 mg) and grade 3 diarrhea (1/6 at 400 mg), defining MTD = 300 mg/day [4]

[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.

[4]. Clin Cancer Res . 2011 Jul 1;17(13):4389-99.

4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone is a N-arylpiperazine.
Dovitinib is an orally active small molecule that exhibits potent inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis. Preclinical data show that dovitinib works to inhibit multiple kinases associated with different cancers, including acute myeloid leukemia (AML) and multiple myeloma. Chiron currently has three ongoing Phase I clinical trials for dovitinib.
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.
Dovitinib is a benzimidazole-quinolinone compound and receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Dovitinib binds to and inhibits the phosphorylation of type III-V RTKs, such as vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) that promote tumor cell proliferation and survival in certain cancer cells. In addition, this agent also inhibits other members of the RTK superfamily, including fibroblast growth factor receptor 1 and 3, FMS-like tyrosine kinase 3, stem cell factor receptor (c-KIT), and colony stimulating factor receptor 1. This may further lead to a reduction of cellular proliferation and angiogenesis, and an induction of tumor cell apoptosis.

---

Drug Indication
Investigated for use/treatment in multiple myeloma and solid tumors.

---

Mechanism of Action
Unlike many kinase inhibitors that only target vascular endothelial growth factor (VEGF), Dovitinib inhibits receptors in the fibroblast growth factor (FGF ) pathway, as well as VEGF and platelet-derived growth factor (PDGF). FGF receptor tyrosine kinase inhibition is potentially of therapeutic significance to a group of myeloma patients whose cancer cells express high levels of surface FGF receptors.

---

Dovitinib (TKI-258, CHIR-258) is a multi-targeted tyrosine kinase inhibitor targeting FGFRs, VEGFRs, and PDGFRs, developed for FGFR-driven cancers (e.g., multiple myeloma, bladder cancer) and angiogenesis-dependent tumors (e.g., HCC, lung cancer) [1][2][3][4]
- Its mechanism involves binding to the ATP-binding pockets of target kinases, inhibiting tyrosine kinase activation and downstream signaling (FGFR/VEGFR/PDGFR: ERK/AKT), thereby blocking cell proliferation, inducing apoptosis, and suppressing angiogenesis [1][3][4]
- It showed clinical activity in advanced solid tumors (partial response in 4.8% patients) and preclinical efficacy in multiple xenograft models, supporting its potential for multi-type cancer treatment [1][4]

C21H21FN6O

392.43

392.176

C, 64.27; H, 5.39; F, 4.84; N, 21.42; O, 4.08

405169-16-6

Dovitinib lactate;692737-80-7;Dovitinib dilactic acid;852433-84-2;Dovitinib-d8;1246819-84-0;Dovitinib lactate hydrate;915769-50-5

135398510

Light yellow to green yellow solid powder

1.4±0.1 g/cm3

1.691

1.59

94.04

3

6

2

29

678

0

FC1=C([H])C([H])=C([H])C2=C1C([H])=C(C(N2N([H])[H])=O)C1=NC2C([H])=C([H])C(=C([H])C=2N1[H])N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H]

PIQCTGMSNWUMAF-UHFFFAOYSA-N

InChI=1S/C21H21FN6O/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/h2-6,11H,7-10H2,1H3,(H,24,25)(H3,23,26,29)

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

TKI-258; CHIR-258; TKI258; TKI-258; Dovitinib; 405169-16-6; CHIR-258; TKI-258; 4-Amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one; Dovitinib [INN]; Dovitinib (TKI-258, CHIR-258); Dovitinib lactate; TKI 258; CHIR258; CHIR-258; CHIR 258; Dovitinib lactate

2934.99.03.00

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.37 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。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (6.37 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。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (6.37 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 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

---

配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/kg

---

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。