Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling
Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling
复制标题
DOI：
10.1158/0008-5472.can-05-0574
复制
发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Daub, H
中科院分区：
文献类型：
--
作者：
Godl, K;Gruss, OJ;Daub, H
关于分子药物作用的知识对于开发用于癌症治疗的蛋白激酶抑制剂至关重要。在这里，我们建立了一种化学蛋白质组学方法来分析抗癌药物SU6668， SU6668最初被设计为参与肿瘤血管化的受体酪氨酸激酶的选择性抑制剂。通过将固定化的SU6668结合质谱法用于细胞药物靶点的亲和力捕获，我们确定了SU6668以前未知的靶点，包括极光激酶和tank结合激酶1。重要的是，SU6668诱导的细胞周期阻滞可能归因于极光激酶活性的抑制。此外，SU6668通过干扰tank结合激酶i介导的信号传递，有效抑制抗病毒和炎症反应。这些结果显示了化学蛋白质组学的潜力，为开发有效的激酶抑制剂提供了基础，这些抑制剂通过同时靶向与癌症进展相关的确定的丝氨酸/苏氨酸和酪氨酸激酶，结合了意想不到的生物作用模式。
Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase I-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.