Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions
| Autor: | David Covini, Christian Dank, Gerd Bader, Andreas Schrenk, Alessio Ciulli, Heribert Arnhof, Joerg Rinnenthal, Helmut Berger, Maria Rieger, Mark Pearson, Peter Greb, Jale Karolyi-Özguer, Elisabeth Traxler, Nicole Trainor, Teresa Gmaschitz, Markus Spina, Vanessa Roessler, Johannes Popow, Peter Ettmayer, Andreas Zoephel, Darryl B. McConnell, Manfred Koegl, Corinna Wieshofer, Steffen Steurer |
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| Rok vydání: | 2019 |
| Předmět: |
PTK2
Protein degradation Ligands 01 natural sciences Focal adhesion 03 medical and health sciences RNA interference Cell Line Tumor Drug Discovery Humans Protein Kinase Inhibitors Cell Proliferation 030304 developmental biology 0303 health sciences Chemistry Kinase Cell growth Cereblon Recombinant Proteins 0104 chemical sciences Cell biology 010404 medicinal & biomolecular chemistry Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Proteolysis Molecular Medicine RNA Interference Tyrosine kinase |
| Zdroj: | Journal of Medicinal Chemistry. 62:2508-2520 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 DC50 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. |
| Databáze: | OpenAIRE |
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