Jiang Zongru, Wang Li, Liu Xuesong, Chen Cheng, Wang Beilei, Wang Wenliang, Hu Chen, Yu Kailin, Qi Ziping, Liu Qingwang, Wang Aoli, Liu Jing, Hong Guangchen, Wang Wenchao, Liu Qingsong
High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
University of Science and Technology of China, Hefei 230026, China.
Acta Pharm Sin B. 2020 Mar;10(3):488-497. doi: 10.1016/j.apsb.2019.10.004. Epub 2019 Oct 18.
Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC = 66 nmol/L) and VEGFR2 autophosphorylation in cells (ECs ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy and exhibited good PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.
血管生成是肿瘤生长、侵袭和转移过程中的一个重要环节。靶向肿瘤血管生成途径的血管内皮生长因子受体2（VEGFR2）抑制剂已广泛应用于临床癌症治疗。然而，目前大多数使用的VEGFR2激酶抑制剂都是多靶点抑制剂，这可能会导致与靶点相关的副作用，从而限制了临床耐受性。从基础研究和临床应用的角度来看，仍然迫切需要高选择性的VEGFR抑制剂。在此，我们报告了一种新型VEGFR2抑制剂（CHMFL-VEGFR2-002）的发现和特性，该抑制剂在包括血小板衍生生长因子受体（PDGFRs）、成纤维细胞生长因子受体（FGFRs）、集落刺激因子1受体（CSF1R）等结构相近的激酶中表现出高选择性。CHMFL-VEGFR2-002在生化实验中对VEGFR2激酶显示出强效抑制活性（IC = 66 nmol/L），在细胞中对VEGFR2自身磷酸化有抑制作用（EC50 ∼100 nmol/L），并且对VEGFR2转化的BaF3细胞具有强效抗增殖作用（GI50 = 150 nmol/L）。此外，CHMFL-VEGFR2-002还显示出良好的抗血管生成功效，并且具有良好的药代动力学特征，生物利用度超过49%，在斑马鱼和小鼠模型中均具有抗血管生成功效且无明显毒性。这些结果表明，CHMFL-VEGFR2-002可能是剖析VEGFR2激酶新功能的有用研究工具，也是癌症治疗中潜在的抗血管生成药物。
