Vorolanib
(Synonyms: CM082; X-82) 目录号 : GC38380
Vorolanib（X-82；CM082）是一种具口服活性的血管内皮生长因子受体（VEGFR）和血小板衍生生长因子受体（PDGFR）的多激酶双重抑制剂，IC50值分别为0.052μM、0.26 μM。
Cas No.:1013920-15-4
Sample solution is provided at 25 µL, 10mM.
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Vorolanib (X-82; CM082) is an orally active dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) multikinases with IC50 values of 0.052μM and 0.26μM, respectively[1]. Vorolanib is a novel tyrosine receptor kinase inhibitor with antiangiogenic and antitumor activities[2]. Vorolanib is a potential inhibitor of ATP-binding cassette (ABC) transporters with the potential to reverse multidrug resistance (MDR)[3].
In vitro, treatment of MDR cells (S1-MI-80 and H460/MX20) with vorolanib (0-100μM) for 96 h inhibited [125I]-IAAP photoaffinity labeling, increased ABCG2 ATPase activity, and reduced rhodamine 123 (Rho 123) efflux[3]. Treatment of HUVEC cells with vorolanib (10µM) for 48h significantly inhibited the proliferation, migration, invasion, and tube formation of HUVECs stimulated with rHuVEGF165[4]. Treatment of HUVEC cells with Vorolanib (0.01, 0.1, 1µM) inhibited cell growth with an IC50 of 0.031±0.005µM, inhibited phosphorylation of VEGFR and downstream signaling molecules, and inhibited angiogenesis and cell migration[5].
In vivo, subcutaneous injection of Vorolanib (80, 160mg/kg) in mice inoculated with H3255 cells slowed tumor growth and significantly inhibited phosphorylation of ERK1/2 and AKT[5]. Oral treatment of rats with choroidal neovascularization (CNV) model with Vorolanib (10, 30mg/kg) reduced CNV leakage, caused regression of CNV lesions, and reduced p-VEGFR-2 aggregation in the retinal pigment epithelium and outer plexiform layer[6]. Oral treatment of mice with retinal detachment with Vorolanib (40mg/kg) did not result in a decrease in retinal and outer nuclear layer (ONL) thickness, indicating a protective effect against photoreceptor degeneration[7].
References:
[1]Fabre M, Mateo L, Lamaa D, et al. Recent advances in age-related macular degeneration therapies[J]. Molecules, 2022, 27(16): 5089.
[2]Liang C, Yuan X, Shen Z, et al. Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity[J]. Molecular Therapy-Oncolytics, 2022, 24: 577-584.
[3]Xu L, Huang J, Liu J, et al. CM082 enhances the efficacy of chemotherapeutic drugs by inhibiting the drug efflux function of ABCG2[J]. Molecular Therapy-Oncolytics, 2020, 16: 100-110.
[4]Dan H, Lei X, Huang X, et al. CM082, a novel VEGF receptor tyrosine kinase inhibitor, can inhibit angiogenesis in vitro and in vivo[J]. Microvascular Research, 2021, 136: 104146.
[5]Zhang K, Wang L, Wei A, et al. CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo[J]. Thoracic cancer, 2020, 11(6): 1566-1577.
[6]Ren C, Shi H, Jiang J, et al. The effect of CM082, an oral tyrosine kinase inhibitor, on experimental choroidal neovascularization in rats[J]. Journal of Ophthalmology, 2017, 2017(1): 6145651.
[7]Howard-Sparks M, Saim S, Farjo R, et al. Neuroprotective effect of tyrosine kinase inhibitor vorolanib in a mouse model of retinal detachment[J]. Investigative Ophthalmology & Visual Science, 2023, 64(8): 2829-2829.
Vorolanib（X-82；CM082）是一种具口服活性的血管内皮生长因子受体（VEGFR）和血小板衍生生长因子受体（PDGFR）的多激酶双重抑制剂，IC50值分别为0.052μM、0.26 μM[1]。Vorolanib是一种新型酪氨酸受体激酶受体抑制剂，具有抗血管生成和抗肿瘤的活性[2]。Vorolanib是一种潜在的ATP结合盒（ABC）转运蛋白抑制剂，有可能逆转多种药物耐药性（MDR）[3]。
在体外，Vorolanib（0-100µM）处理MDR细胞（S1-MI-80和H460/MX20）96h， 抑制了[125I]-IAAP光亲和标记，增加了ABCG2 ATPase的活性，减少了罗丹明123（Rho 123）的流出[3]。Vorolanib（10µM）处理HUVEC细胞48h，显著抑制了用rHuVEGF165刺激HUVEC引起的增殖、迁移、侵袭和管形成[4]。Vorolanib（0.01、0.1、1µM）处理HUVEC细胞， 抑制了细胞生长，IC50为0.031±0.005µM，抑制了VEGFR和下游信号分子的磷酸化，抑制了血管形成和细胞迁移[5]。
在体内，Vorolanib（80、160mg/kg）通过皮下注射治疗接种了H3255细胞的小鼠，减缓了肿瘤的生长，并显著抑制了ERK1/2和AKT的磷酸化[5]。Vorolanib（10、30mg/kg）通过口服治疗脉络膜新生血管（CNV）模型大鼠，减少了CNV 渗漏，引起CNV病变的消退，减少了视网膜色素上皮和外丛状层中p-VEGFR-2的聚集[6]。Vorolanib（40mg/kg）通过口服治疗视网膜脱离小鼠，视网膜和外核层（ONL）厚度没有下降，表明对光感受器变性具有保护作用[7]。
| Cell experiment [1]: | |
Cell lines | Human umbilical vein endothelial cells (HUVECs) |
Preparation Method | HUVECs were seeded at a density of 2×103 cells per well in a 96-well plate. After 24h, cells were incubated with or without 0.1%DMSO and 10μM Vorolanib, respectively. Thirty minutes later, cells were treated with or without a final concentration of 50ng/ml recombinant human VEGF165 for 48h. Then, the cell viability was measured using the CCK8 method. |
Reaction Conditions | 10µM; 48h |
Applications | 0.1% DMSO had no effect on HUVEC proliferation, 50 ng/ml rHuVEGF165 induced HUVEC proliferation, and 10μM Vorolanib inhibited HUVEC proliferation. |
| Animal experiment [2]: | |
Animal models | Female BALB/c nude mice |
Preparation Method | H3255 cells were subcutaneously injected into the right flank of the mice. When the tumor volume reached approximately 100 mm3, the mice were randomly assigned to six groups and treated with DMSO, Vorolanib (80mg/kg b.i.d.), Vorolanib (160mg/kg b.i.d.), sunitinib (50mg/kg q.d.), gefitinib (10 mg/kg q.d.), and gefitinib (10 mg/kg q.d.) combined with Vorolanib (80mg/kg b.i.d.), respectively. Bodyweight and tumor volume of the mice were measured every three days for 21 days. |
Dosage form | 80、160mg/kg; s.c. |
Applications | Vorolanib slowed tumor growth, and significantly inhibited the phosphorylation of ERK1/2 and AKT. |
References: [1]Dan H, Lei X, Huang X, et al. CM082, a novel VEGF receptor tyrosine kinase inhibitor, can inhibit angiogenesis in vitro and in vivo[J]. Microvascular Research, 2021, 136: 104146. [2]Zhang K, Wang L, Wei A, et al. CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non‐small cell lung cancer in vitro and in vivo[J]. Thoracic cancer, 2020, 11(6): 1566-1577. | |
| Cas No. | 1013920-15-4 | SDF | |
| 别名 | CM082; X-82 | ||
| Canonical SMILES | O=C1/C(C2=CC(F)=CC=C2N1)=C/C(NC(C)=C3C(N[C@@H]4CN(C(N(C)C)=O)CC4)=O)=C3C | ||
| 分子式 | C23H26FN5O3 | 分子量 | 439.48 |
| 溶解度 | DMSO: 27 mg/mL (61.44 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2754 mL | 11.3771 mL | 22.7542 mL |
| 5 mM | 0.4551 mL | 2.2754 mL | 4.5508 mL |
| 10 mM | 0.2275 mL | 1.1377 mL | 2.2754 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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