Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor
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DOI：
10.1007/978-3-540-33177-3_23
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
S. Wedge;J. Jürgensmeier
中科院分区：
文献类型：
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作者：
S. Wedge;J. Jürgensmeier
血管内皮生长因子（VEGF）信号传导是肿瘤新生血管生长、存活和毛细血管通透性的关键刺激物，这些对实体瘤进展至关重要。诱导血管生成表型的细胞内信号传导反应依赖于VEGF与内皮上特异性跨膜受体的结合和内源性受体酪氨酸激酶活性的激活。抑制这种信号传导途径的尝试包括螯合配体或阻碍其与受体相互作用的生物制药方法。一种替代策略是使用酪氨酸激酶抑制剂，其可能提供更完全的VEGFR信号传导阻断。这些低分子量抑制剂可以选择具有口服生物利用度的药物，并制成片剂用于每日给药，这可以为患者提供更大的便利。本文综述了VEGFR-2酪氨酸激酶的结构特点，利用ATP竞争性抑制剂，以防止其激活，从而废除信号。使用VEGF受体酪氨酸激酶的高效抑制剂AZD 2171产生的临床前数据用于说明抑制生理和病理VEGF信号传导的后果，包括在体内广泛的肿瘤模型中的显著生长抑制活性。目前开发的许多抑制剂的性质也与其相关的临床研究结果进行了审查。虽然已经出现了具有一系列药理学特征的化合物，但只有结合了高效力、选择性和良好药代动力学性质的联合收割机抑制剂才有可能在临床上稳健地测试小分子VEGFR信号传导抑制剂概念。
Vascular endothelial growth factor (VEGF) signalling is a key stimulant of tumour neovascular growth, survival and capillary permeability, which are critical to solid tumour progression. The intracellular signalling responses that induce an angiogenic phenotype are dependent upon VEGF binding to specific transmembrane receptors on the endothelium and activation of intrinsic receptor tyrosine kinase activity. Attempts to inhibit this signalling pathway have included biopharmaceutical approaches that sequester ligand or obstruct its interaction with receptors. An alternative strategy is to use tyrosine kinase inhibitors that could potentially provide a more complete blockade of VEGFR signalling. These low-molecular-weight inhibitors can be selected with oral bioavailability and prepared as tablets for daily dosing, which may afford greater patient convenience. This review describes the structural features of VEGFR-2 tyrosine kinase that are exploited by ATP-competitive inhibitors to prevent its activation and thereby abrogate signalling. Preclinical data generated with a highly potent inhibitor of the VEGF receptor tyrosine kinases, AZD2171, are used to illustrate the consequences of inhibiting physiological and pathological VEGF signalling, including significant growth inhibitory activity across a wide range of tumour models in vivo. The properties of the many inhibitors in current development are also reviewed with their associated clinical findings. Whilst compounds with a range of pharmacological profiles have emerged, only inhibitors that combine high potency, selectivity and good pharmacokinetic properties are likely to test the smallmolecule VEGFR signalling inhibitor concept robustly in the clinic.