Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent
Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent
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发现高选择性 VEGFR2 激酶抑制剂 CHMFL-VEGFR2-002 作为新型抗血管生成剂
DOI：
10.1016/j.apsb.2019.10.004
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发表时间：
2020-03-01
影响因子：
14.5
通讯作者：
Liu, Qingsong
中科院分区：
文献类型：
--
作者：
Jiang, Zongru;Wang, Li;Liu, Qingsong
血管生成是肿瘤生长、侵袭和转移的重要过程。以肿瘤血管生成通路为靶点的血管内皮生长因子受体2（VEGF receptor 2，VEGFR 2）抑制剂已广泛应用于临床肿瘤治疗。然而，目前使用的大多数VEGFR 2激酶抑制剂是多靶点抑制剂，这可能导致靶点相关的副作用，因此限制了临床耐受性。从基础研究和临床应用的角度来看，高选择性的VEGFR抑制剂仍然具有很高的需求。在这里，我们报告了一种新的VEGFR 2抑制剂的发现和表征，（CHMFL-VEGFR 2 -002），其在包括PDGFR、FGFR、CSF 1 R、CHMFL-VEGFR 2 -002在生化测定中显示出对VEGFR 2激酶的有效抑制活性（IC 50 = 66 nmol/L）和细胞中VEGFR 2自磷酸化（EC（50）类似于100 nmol/L）以及对VEGFR 2转化的BaF 3细胞的强效抗增殖作用（GI（50）= 150 nmol/L）。此外，CHMFL-VEGFR 2 -002还在体外显示出良好的抗血管生成功效，并在斑马鱼和小鼠模型中显示出良好的体内PK（药代动力学）特征，生物利用度超过49%，并且具有抗血管生成功效，而没有明显的毒性。这些结果表明，CHMFL-VEGFR 2 -002可能是一个有用的研究工具，解剖VEGFR 2激酶的新功能，以及一个潜在的抗血管生成剂的癌症治疗。(C)2020中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
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 (IC50 = 66 nmol/L) and VEGFR2 autophosphorylation in cells (EC(50)s similar to 100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI(50) = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo 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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.