Autoinhibited proteins as promising drug targets

Current drug discovery efforts generally focus on a limited number of protein classes, typically including proteins with well‐defined catalytic active sites (e.g., kinases) or ligand binding sites (e.g., G protein‐coupled receptors). Nevertheless, many clinically important pathways are mediated by proteins with no such obvious targets for small molecule inhibitors. Allosteric inhibitors offer an alternative approach to inhibition of protein activities, particularly for proteins that undergo conformational changes as part of their activity cycle. Proteins regulated by autoinhibitory domains represent one broad class of proteins that meets this criterion. In this article, we discuss the potential of autoinhibited proteins as targets for allosteric inhibitors and describe two examples of small molecules that act by stabilizing native autoinhibited conformations of their targets. We propose that proteins regulated by autoinhibition may be generally amenable to allosteric inhibition by small molecules that stabilize the native, autoinhibited fold. © 2004 Wiley‐Liss, Inc.