A new mechanism of action for ATP-competitive kinase inhibitors is reported this week in Nature Chemical Biology. This mechanism should be considered when evaluating the efficacy of these drugs for clinical applications.
Kinases are enzymes that play essential roles in transmitting signals through cells for normal processes and in diseases such as cancer. Because of their central importance in cellular communication, and the fact that they are enzymes, they are often targets of interest for drug discovery efforts. One common approach to targeting kinases is via the generation of ATP-competitive inhibitors, or small molecules that compete with ATP for binding to the kinase and thereby inhibit the activity of the kinase.
Laurence Pearl, Paul Workman and colleagues report a new mechanism by which ATP-competitive inhibitors inhibit the activity of kinases. The authors show that a co-chaperone protein called Cdc37 interacts with many kinases to promote their folding by targeting them to the Hsp90 chaperone-or protein folding-machinery, thereby protecting the kinases from cellular degradation pathways. Surprisingly, application of ATP-competitive inhibitors (for example, vemurafenib and lapatinib) deprives access of kinases to the protein-folding machinery and promotes their degradation. Therefore, in addition to inhibiting the enzymatic activity of kinases, ATP-competitive inhibitors can reduce the number of active kinases in a cell by promoting their degradation. The authors suggest that this new mechanism of action for a common drug class might need to be considered when evaluating the clinical efficacy of these important drugs.