Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Johannes Popow, Heribert Arnhof, Gerd Bader, Helmut Berger, Alessio Ciulli, David Covini, Christian Dank, Teresa Gmaschitz, Peter Greb, Jale Karolyi-Özguer, Manfred Koegl, Darryl B. McConnell, Mark Pearson, Maria Rieger, Joerg Rinnenthal, Vanessa Roessler, Andreas Schrenk, Markus Spina, Steffen Steurer, Nicole TrainorElisabeth Traxler, Corinna Wieshofer, Andreas Zoephel, Peter Ettmayer

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
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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 50 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.

Original languageEnglish
Pages (from-to)2508–2520
Number of pages13
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
Early online date9 Feb 2019
DOIs
Publication statusPublished - 14 Mar 2019

Keywords

  • PROTACs
  • protein degradation
  • E3 ubiquitin ligases
  • kinases
  • van Hippel-Lindau
  • Cereblon
  • CRBN

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