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.