Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?

The ATP site of kinases displays
remarkable conformational flexibility
when accommodating chemically diverse small molecule inhibitors. The
so-called activation segment, whose conformation controls catalytic
activity and access to the substrate binding pocket, can undergo a
large conformational change with the active state assuming a ‘DFG-in’
and an inactive state assuming a ‘DFG-out’ conformation.
Compounds that preferentially bind to the DFG-out conformation are
typically called ‘type II’ inhibitors in contrast to ‘type
I’ inhibitors that bind to the DFG-in conformation. This review
surveys the large number of type II inhibitors that have been developed
and provides an analysis of their crystallographically determined
binding modes. Using a small library of type II inhibitors, we demonstrate
that more than 200 kinases can be targeted, suggesting that type II
inhibitors may not be intrinsically more selective than type I inhibitors.

激酶的ATP结合位点在适配化学结构多样的小分子抑制剂时，展现出显著的构象灵活性。所谓的激活段（activation segment），其构象可调控激酶的催化活性以及底物结合口袋的可及性，能够发生大幅构象变化：活性态呈现为DFG入（DFG-in）构象，而非活性态则呈现为DFG出（DFG-out）构象。相较于结合DFG入构象的I型抑制剂，优先结合DFG出构象的化合物通常被称为II型抑制剂。本综述梳理了已开发的大量II型抑制剂，并对其经晶体学解析得到的结合模式进行了系统分析。本研究通过构建小型II型抑制剂库，证实II型抑制剂可靶向超过200种激酶，这提示II型抑制剂本质上并不比I型抑制剂具有更高的选择性。