Multi-Kinase Inhibitors
Multi-Kinase Inhibitors
复制标题
DOI：
10.2174/0929867321666141216125528
复制
发表时间：
2015-01-01
影响因子：
4.1
通讯作者：
Bottegoni, Giovanni
中科院分区：
文献类型：
--
作者：
Garuti, Laura;Roberti, Marinella;Bottegoni, Giovanni
许多单激酶抑制剂的局限性可以通过具有多靶点作用的药物来克服。靶向多种激酶的一个重要优势是由于协同效应而增加了效力。此外，这种方法可以减少产生耐药性的可能性。几种多靶点药物已被设计为单激酶抑制剂，并且由于激酶的 ATP 结合位点之间的结构同源性而被发现是多靶点抑制剂。在其他情况下，这些抑制剂是通过优化有效的单个抑制剂或通过选择性配体的组合来获得的。此外，一些不可逆抑制剂作用于不同的激酶并共价修饰位于 ATP 结合袋附近的半胱氨酸残基。本综述报道了多激酶抑制剂的最新实例，重点关注化学结构、构效关系 (SAR) 和生物活性。这些抑制剂经过适当替代后可用于设计其他多靶点药物。虚拟分子对接将提示分子的潜在靶标，此外，结合药效团组合和筛选方法可能有助于发现更有效的多激酶抑制剂。
The limitations of many mono-kinase inhibitors can be overcome by agents with multi-target action. An important advantage of targeting more than one kinase, is an increase in potency, due to the synergistic effect. Moreover, this approach can reduce the possibility of developing drug resistance. Several multitarget agents have been designed as single kinase inhibitors and found to be multi-target inhibitors because of the structural homology among the ATP-binding site of kinases. In other cases, these inhibitors have been obtained by optimization of potent individual inhibitors or by combination of selective ligands. Also some irreversible inhibitors act on different kinases and covalently modify the cysteine residues located near the ATP-binding pocket. In this review the most recent examples of multi-kinase inhibitors are reported, focusing on chemical structures, structure-activity relationship (SAR) and biological activity. These inhibitors, suitably substituted, could be used in designing other multitarget agents. Virtual molecular docking would suggest potential targets of molecules, moreover combining pharmacophore combination and screening methods could probably help in the discovery of more potent multikinase inhibitors.