6GCR

Focal Adhesion Kinase catalytic domain in complex with irreversible inhibitor

Summary for 6GCR

• Entry DOI: 10.2210/pdb6gcr/pdb
• Related: 6GCW 6GCX
• Descriptor: Focal adhesion kinase 1, 2-[[2-[[4-[[[3,4-bis(oxidanylidene)-2-[2-(propanoylamino)ethylamino]cyclobuten-1-yl]amino]methyl]phenyl]amino]-5-chloranyl-pyrimidin-4-yl]amino]-~{N}-methyl-benzamide (3 entities in total)
• Functional Keywords: focal adhesion kinase cell adhesion signalling irreversible inhibitor 2, 4-pyrimidine derivatives, cell adhesion
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 1
• Total formula weight: 32308.84

Authors

Yen-Pon, E.,Li, B.,Acebron-Garcia de Eulate, M.,Tomkiewicz-Raulet, C.,Dawson, J.,Lietha, D.,Frame, M.C.,Coumoul, X.,Garbay, C.,Etheve-Quelquejeu, M.,Chen, H. (deposition date: 2018-04-19, release date: 2019-05-01, Last modification date: 2024-11-06)

Primary citation

Yen-Pon, E.,Li, B.,Acebron-Garcia-de-Eulate, M.,Tomkiewicz-Raulet, C.,Dawson, J.,Lietha, D.,Frame, M.C.,Coumoul, X.,Garbay, C.,Etheve-Quelquejeu, M.,Chen, H.
Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase.
Acs Chem.Biol., 13:2067-2073, 2018

PubMed 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.

PubMed: 29897729
DOI: 10.1021/acschembio.8b00250

Experimental method

X-RAY DIFFRACTION (2.3 Å)