靶向非活性激酶DFG-out变构结合位点的研究进展

目前大多数激酶抑制剂是通过模拟ATP的结构,以识别激酶的活性构象来竞争性结合于ATP结合位点,从而抑制激酶的自磷酸化和下游的信号传导。然而,最近人们对已上市药物甲磺酸伊马替尼、尼罗替尼及对甲苯磺酸索拉非尼的晶体结构研究发现,在非活性激酶中ATP结合位点的相邻位置存在着第二个能与激酶抑制剂结合的位点———DFG-out变构结合位点。该位点的发现为以蛋白激酶为靶标的小分子激酶抑制剂的设计与开发指明了新的方向,成为抗肿瘤研究领域的新热点之一。因此,本文对非活性激酶的DFG-out变构结合位点的发现、非活性激酶与其抑制剂的结合方式及处于临床研究阶段的非活性激酶抑制剂进行了综述。

Advances in the research of tageting DFG-out allosteric binding site of inactive kinases

Up to nowadays,a majority of kinase inhibitors identify the activity conformation of protein kinase to integrate competitively with ATP binding site by simulating the structure of ATP.In this way,kinase inhibitors can inhibit kinase autophosphorylation and restrain signal transduction of downstream.However,the crystal structures of imatinib mesylate,nilotnib and sorafenib tosylate have revealed a secondary binding site adjacent to the ATP binding site,which is also bound by kinase inhibitors,known as the DFG-out allosteric binding site,in the inactive conformation of protein kinase.The discovery of the site has pointed out a new direction for the design and development of small molecule kinase inhibitors,which takes protein kinase as a target.This becomes a new hotspot in antineoplastic research field.In this paper,we reviewed the discovery and inhibitors of the DFG-out allosteric binding site,and the binding mode between inactive kinases,as well as the inactive kinase inhibitors in clinical studies.