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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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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. | |
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]。
| 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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| 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 | ||||||||||
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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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Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity
Mol Ther Oncolytics 2022 Jan 10;24:577-584.PMID:35252556DOI:10.1016/j.omto.2022.01.001.
Vorolanib (CM082) is a multi-targeted tyrosine kinase receptor inhibitor with a short half-life and limited tissue accumulation that has been shown to reduce choroidal neovascularization in rats. In this preclinical study, Vorolanib demonstrated competitive binding and inhibitory activities with KDR, PDGFRβ, FLT3, and C-Kit, and inhibited RET and AMPKα1 more weakly than sunitinib, indicating more stringent kinase selectivity. Vorolanib inhibited vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) and HUVEC tube formation in vitro. In mouse xenograft models, Vorolanib inhibited tumor growth of MV-4-11, A549, 786-O, HT-29, BxPC-3, and A375 cells in a dose-dependent fashion. Complete tumor regression was achieved in the MV-4-11 xenograft model. No significant toxicities were observed in Vorolanib groups, whereas a significant negative impact on body weights was observed in the sunitinib group at a dose of 40 mg/kg qd. Overall, Vorolanib is a novel multi-kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity that is potentially less toxic than other similar kinase inhibitors.
Vorolanib (X-82), an oral anti-VEGFR/PDGFR/CSF1R tyrosine kinase inhibitor, with everolimus in solid tumors: results of a phase I study
Invest New Drugs 2021 Oct;39(5):1298-1305.PMID:33738668DOI:10.1007/s10637-021-01093-7.
Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of Vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of Vorolanib/everolimus. Oral Vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is Vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.
Efficacy and safety of Vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)
Eur J Cancer 2023 Jan;178:205-215.PMID:36459768DOI:10.1016/j.ejca.2022.10.025.
Background: Vorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of Vorolanib and everolimus or Vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC). Patients and methods: Patients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of Vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1. Results: Between 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the Vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the Vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, Vorolanib group and everolimus group, respectively. Conclusions: The addition of Vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile. Trial registration: ClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.
Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: An open-label, phase I dose escalation and dose expansion trial
Chin J Cancer Res 2021 Feb 28;33(1):103-114.PMID:33707933DOI:10.21147/j.issn.1000-9604.2021.01.11.
Objective: This study evaluated the safety and preliminary efficacy of Vorolanib, a novel tyrosine kinase inhibitor, for treatment of patients with advanced solid tumors. Methods: During dose escalation, patients received increasing doses of oral Vorolanib (50-250 mg once daily) in cycles of four weeks for up to one year. During dose expansion, patients received recommended doses (100 and 200 mg) in 4-week cycles. The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose (RP2D). The severity and type of adverse drug reactions (ADRs) were assessed using the Common Terminology Criteria for Adverse Events version 4.0. The second endpoint was preliminary efficacy in terms of objective response and progression-free survival (PFS). Results: No dose-limiting toxicity occurred during dose escalation (50-250 mg). Five (26.3%) patients in the escalation cohort (n=19) and 12 (48.0%) in the expansion cohort (n=25) experienced grade 3 ADRs. The most common ADRs were hair color changes, fatigue, portal hypertension, hypertriglyceridemia, and proteinuria. During dose expansion, the patients treated with 200 mg and 100 mg (once daily) showed an objective response rate of 22.2% and 5.9%, respectively; the disease control rate was 88.9% and 73.3%, respectively; the median PFS was 9.9 [95% confidence interval (95% CI): 7.4-not reached] months and 3.8 (95% CI: 1.9-not reached) months, respectively. Conclusions: Oral Vorolanib at a dose of 200 mg (once daily) exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors. The RP2D for Vorolanib was determined to be 200 mg as a daily regimen.
Phase 1 trial of Vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma
EBioMedicine 2020 May;55:102755.PMID:32335374DOI:10.1016/j.ebiom.2020.102755.
Background: Vorolanib (X-82, CM082) is a multi-target tyrosine kinase inhibitor. This study aimed to evaluate the tolerability, safety, pharmacokinetics and antitumor activities of Vorolanib plus everolimus (an inhibitor of mammalian target of rapamycin). Methods: Patients had histologically or cytologically confirmed advanced RCC and failed with standard therapy were eligible for this study. Dose-escalated combinations of Vorolanib (100, 150 or 200 mg once daily) with everolimus (5 mg once daily) were administered on 28-day cycles until disease progression or unacceptable toxicity using a conventional 3 + 3 dose-escalation design. Findings: 22 patients (100 mg n = 4, 150 mg n = 3, 200 mg n = 15) were enrolled. Only one patient experienced dose-limiting toxicity (DLT, grade 4 thrombocytopenia) in the Vorolanib 200 mg combination cohort, and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events were proteinuria (100%), leukopenia (77%), hypercholesterolaemia (77%), increased low-density lipoprotein (68%), hypertriglyceridaemia (64%), hyperglycaemia (59%), and fatigue (55%). Most treatment-related adverse events were grade 1 to 2, with grade 3 or higher toxicities mostly seen in the 200 mg cohort. Single dosing of Vorolanib demonstrated dose-proportional increases in the Cmax and AUC, and observed short t1/2z ranging from 4.74±1.44 to 12.89±7.49 h. The pharmacokinetic parameters for everolimus were similar among all cohorts. Of 19 evaluable patients, the ORR and DCR was 32% (n = 6, 95% CI, 13-57%) and 100% (95% CI, 82-100%), respectively. Interpretation: Combination therapy of Vorolanib 200 mg plus everolimus 5 mg once daily is potentially effective with potential activity. Further evaluation of the combination in advanced RCC patients is ongoing (NCT03095040). Funding: Betta Pharmaceutical Co., Ltd., Hangzhou, China.