Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2

The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases.