Rational design of inhibitors that bind to inactive kinase conformations
Rational design of inhibitors that bind to inactive kinase conformations
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DOI：
10.1038/nchembio799
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发表时间：
2006-07-01
影响因子：
14.8
通讯作者：
Gray, NS
中科院分区：
文献类型：
--
作者：
Liu, Y;Gray, NS
到目前为止，大多数已开发的激酶抑制剂被称为I型抑制剂，其目标是激酶活性构象的ATP结合位点，其中激活环被磷酸化。最近，被称为II型抑制剂的伊马替尼（STI571）、BIRB796和索拉非尼（BAY43-9006）等抑制剂的晶体结构揭示了一种新的结合模式，该模式利用紧邻ATP占据区域的额外结合位点。这个口袋可以通过激活环重排进入，这是激酶在非活性构象中的特征。在这里，我们对已知的人类II型抑制剂的结合模式进行了结构分析，并证明它们符合目前用于设计新一代激酶抑制剂的药效团模型。
The majority of kinase inhibitors that have been developed so far-known as type I inhibitors-target the ATP binding site of the kinase in its active conformation, in which the activation loop is phosphorylated. Recently, crystal structures of inhibitors such as imatinib (STI571), BIRB796 and sorafenib (BAY43-9006)-known as type II inhibitors - have revealed a new binding mode that exploits an additional binding site immediately adjacent to the region occupied by ATP. This pocket is made accessible by an activation-loop rearrangement that is characteristic of kinases in an inactive conformation. Here, we present a structural analysis of binding modes of known human type II inhibitors and demonstrate that they conform to a pharmacophore model that is currently being used to design a new generation of kinase inhibitors.