1360460-87-2Relevant academic research and scientific papers
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2
Berger, Benedict-Tilman,Amaral, Marta,Kokh, Daria B.,Nunes-Alves, Ariane,Musil, Djordje,Heinrich, Timo,Schr?der, Martin,Neil, Rebecca,Wang, Jing,Navratilova, Iva,Bomke, Joerg,Elkins, Jonathan M.,Müller, Susanne,Frech, Matthias,Wade, Rebecca C.,Knapp, Stefan
, p. 686 - 7,698 (2021/02/16)
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.
