Drug discovery and the human kinome: Recent trends

A major new trend in drugs targeted at protein kinases is the discovery of allosteric modulators. These compounds differ from ATP-centric drugs in that they do not compete with ATP for binding to the catalytic domain, generally acting by inducing conformational changes to modulate activity. They could provide a number of advantages over more classical protein kinase drugs. For example, they are likely to be more selective, since they bind to unique regions of the kinase and may be useful in overcoming resistance that has developed to drugs that compete with ATP. They offer the ability of activating the kinases either by removing factors that inhibit kinase activity or by simply producing changes to the enzyme to foster catalytic activity. Furthermore, they provide more subtle modulation of kinase activity than simply blocking ATP access to inhibit activity. One hurdle to overcome in discovering these compounds is that allosteric modulators may need to inhibit protein–protein interactions; generally difficult to accomplish with small molecules. Despite the technical problems of identifying allosteric modulators, major gains have been made in identifying allosteric inhibitors and activators of the growth factor receptors as well as soluble tyrosine and serine/threonine kinases and some of these drugs are now in various stages of clinical trials. This review will focus on the discovery of novel allosteric modulators of protein kinases and drug discovery approaches that have been employed to identify such compounds.