Vorolanib
(Synonyms: CM082; X-82) 目录号 : GC38380
X-82 (Vorolanib, CM082) is an oral, multikinase, dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with antiangiogenic and antineoplastic activities.
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
X-82 (Vorolanib, CM082) is an oral, multikinase, dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with antiangiogenic and antineoplastic activities.
[1] Johanna C Bendell, et al. Oncologist. 2019 Apr;24(4):455-e121.
| 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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.