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]。