6GCX

Focal Adhesion Kinase catalytic domain in complex with irreversible inhibitor

6GCX の概要

• エントリーDOI: 10.2210/pdb6gcx/pdb
• 関連するPDBエントリー: 6GCR 6GCW
• 分子名称: 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, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: focal adhesion kinase cell adhesion signalling irreversible inhibitor 2, 4-pyrimidine derivatives, cell adhesion
• 由来する生物種: Gallus gallus (Chicken)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32500.97

構造登録者

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. (登録日: 2018-04-19, 公開日: 2019-05-01, 最終更新日: 2024-05-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.553 Å)