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There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.

Original publication




Journal article


Cell Chem Biol

Publication Date





686 - 698.e7


NanoBRET, focal adhesion kinase (FAK), kinase inhibitor, ligand residence time, proline-rich tyrosine kinase 2 (PYK2), structure-kinetic-relationship, τRAMD, Cells, Cultured, Female, Focal Adhesion Kinase 1, HEK293 Cells, Humans, Indoles, Kinetics, Ligands, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors, Sulfonamides