1 research outputs found
Structure-based design, synthesis and characterization of the first irreversible inhibitor of Focal Adhesion Kinase
Focal
Adhesion Kinase signaling pathway and its functions have been involved
in the development and aggressiveness of tumor malignancy, it then
presents a promising cancer therapeutic target. Several reversible
FAK inhibitors have been developed and are being conducted in clinical
trials. On the other hand, irreversible covalent inhibitors would
bring many desirable pharmacological features including high potency
and increased duration of action. Herein we report the structure-guided
development of the first highly potent and irreversible inhibitor
of the FAK kinase. This inhibitor showed a very potent decrease of
autophosphorylation of FAK in squamous cell carcinoma. A cocrystal
structure of the FAK kinase domain in complex with this compound revealed
the inhibitor binding mode within the ATP binding site and confirmed
the covalent linkage between the targeted Cys427 of the protein and
the inhibitor