Mechanisms of Action of Kinase Inhibitors

Vogel et al. (2008) presented a good overview of the mechanisms of action of protein kinase inhibitor. These inhibitors can act by binding directly in the ATP binding site competitively, (type I inhibitors), but they tend to be less specific because of the shared characteristics of the ATP binding pockets among various kinases. More specificity can be attained with type II inhibitors that can extend into an allosteric site next to the ATP pocket and is only available in the inactive (non-phosphorylated) forms of the enzymes. Imatinib is an example of this, with a 200-fold increased potency to the inactive form of the enzyme, observed in cell-based versus enzyme assays. Often, these inhibitors bind with slower off-rate and on-rate due to a requirement for conformational changes.

Type III inhibitors bind to sites distal to the ATP binding site and are often inactive in simple kinase enzyme assays. This apparent inactivity arises because these compounds can bind to the kinase and render it a poor substrate for an activating upstream kinase, thus disabling its activation. As a consequence, a cascade or cell-based assay may be required.

Was this article helpful?

0 0

Post a comment