Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?
Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?
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DOI：
10.1007/s10456-009-9160-6
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发表时间：
2010-03
期刊：
影响因子：
9.8
通讯作者：
Verheul, Henk M. W.
中科院分区：
文献类型：
--
作者：
Gotink, Kristy J.;Verheul, Henk M. W.
酪氨酸激酶是重要的细胞信号蛋白，具有多种生物活性，包括细胞增殖和迁移。多种激酶参与血管生成，包括受体酪氨酸激酶，例如血管内皮生长因子受体。抑制血管生成酪氨酸激酶已被开发为癌症的全身治疗策略。三种抗血管生成酪氨酸激酶抑制剂 (TKI)：舒尼替尼、索拉非尼和帕唑帕尼，对血管生成激酶具有不同的结合能力，最近被批准用于治疗晚期癌症（肾细胞癌、胃肠道间质瘤和肝细胞癌）患者。许多其他抗血管生成 TKI 正在 I-III 期临床试验中进行研究。除了有益的抗肿瘤活性外，还观察到这些药物具有临床耐药性和毒性。在这篇手稿中，我们将概述抗血管生成 TKI 的设计和开发。我们描述了它们的分子结构和分类、作用机制以及对特定激酶信号通路的抑制活性。此外，我们深入了解 TKI 对血管生成激酶的选择性靶向可能在多大程度上有助于临床观察到的抗肿瘤活性、耐药性和毒性。我们认为，加深对抗血管生成 TKI 临床作用机制的了解，以进一步优化其临床疗效至关重要。
Tyrosine kinases are important cellular signaling proteins that have a variety of biological activities including cell proliferation and migration. Multiple kinases are involved in angiogenesis, including receptor tyrosine kinases such as the vascular endothelial growth factor receptor. Inhibition of angiogenic tyrosine kinases has been developed as a systemic treatment strategy for cancer. Three anti-angiogenic tyrosine kinase inhibitors (TKIs), sunitinib, sorafenib and pazopanib, with differential binding capacities to angiogenic kinases were recently approved for treatment of patients with advanced cancer (renal cell cancer, gastro-intestinal stromal tumors, and hepatocellular cancer). Many other anti-angiogenic TKIs are being studied in phase I-III clinical trials. In addition to their beneficial anti-tumor activity, clinical resistance and toxicities have also been observed with these agents. In this manuscript, we will give an overview of the design and development of anti-angiogenic TKIs. We describe their molecular structure and classification, their mechanism of action, and their inhibitory activity against specific kinase signaling pathways. In addition, we provide insight into what extent selective targeting of angiogenic kinases by TKIs may contribute to the clinically observed anti-tumor activity, resistance, and toxicity. We feel that it is of crucial importance to increase our understanding of the clinical mechanism of action of anti-angiogenic TKIs in order to further optimize their clinical efficacy.
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影响因子：
158.5
作者：
Eremina, Vera;Jefferson, J. Ashley;Quaggin, Susan E.
通讯作者：
Quaggin, Susan E.
DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/nrd2792
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
DEVRIES, C;ESCOBEDO, JA;WILLIAMS, LT
通讯作者：
WILLIAMS, LT