Kinase Inhibitors - Stabilizing Inactive Enzyme Conformations

Kinase Inhibitors - Stabilizing Inactive Enzyme Conformations 

The availabUity of the DFG-out pocket requires the kinase activation loop to adopt a catalytically deficient conformation in which the ATP binding site becomes partially occluded by the Phe side chain of the DFG motif. While the DFG-out conformation is more favorable in the unphosphorylated kinase, phosphorylation of the activation loop shifts conformational equUibria to the more active DFG-in conformation, increases kinase activity, and often reduces the affinity of type 11 and type 111 inhibitors [1]. Although the search for chemical scaffolds which have affinity for the DFG-out pocket is moving to the forefront of kinase inhibitor research, efforts have been constrained by the lack of high-throughput assay technologies which can identify and discriminate for hgands which bind to and stabihze enzymatically inactive kinase conformation. 

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