1. Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase.
- Author
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Yen-Pon E, Li B, Acebrón-Garcia-de-Eulate M, Tomkiewicz-Raulet C, Dawson J, Lietha D, Frame MC, Coumoul X, Garbay C, Etheve-Quelquejeu M, and Chen H
- Subjects
- Amino Acid Sequence, Animals, Binding Sites drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Focal Adhesion Protein-Tyrosine Kinases chemistry, Focal Adhesion Protein-Tyrosine Kinases metabolism, Humans, Models, Molecular, Neoplasms drug therapy, Phosphorylation drug effects, Protein Kinase Inhibitors chemical synthesis, Sequence Alignment, Drug Design, Focal Adhesion Protein-Tyrosine Kinases antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
- Abstract
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.
- Published
- 2018
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