6I8Z

Crystal structure of PTK2 in complex with BI-4464.

6I8Z の概要

• エントリーDOI: 10.2210/pdb6i8z/pdb
• 分子名称: Focal adhesion kinase 1, 3-methoxy-~{N}-(1-methylpiperidin-1-ium-4-yl)-4-[[4-[(3-oxidanylidene-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide (3 entities in total)
• 機能のキーワード: inhibitor, protein kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32803.73

構造登録者

Bader, G.,Zoephel, A. (登録日: 2018-11-21, 公開日: 2019-02-20, 最終更新日: 2024-11-13)

主引用文献

Popow, J.,Arnhof, H.,Bader, G.,Berger, H.,Ciulli, A.,Covini, D.,Dank, C.,Gmaschitz, T.,Greb, P.,Karolyi-Ozguer, J.,Koegl, M.,McConnell, D.B.,Pearson, M.,Rieger, M.,Rinnenthal, J.,Roessler, V.,Schrenk, A.,Spina, M.,Steurer, S.,Trainor, N.,Traxler, E.,Wieshofer, C.,Zoephel, A.,Ettmayer, P.
Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions.
J.Med.Chem., 62:2508-2520, 2019

PubMed Abstract: Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.

PubMed: 30739444
DOI: 10.1021/acs.jmedchem.8b01826

実験手法

X-RAY DIFFRACTION (1.99 Å)