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Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions
Open accessAbstract
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.
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Metadata
- Authors
- Popow, J., Arnhof, H., Bader, G., Berger, H., Ciulli, A., Covini, D., Dank, C., Gmaschitz, T., Greb, P., Karolyi-Özguer, 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.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- University of Dundee (GB)
- Boehringer Ingelheim RCV GmbH & Co KG, 1221 Vienna, Austria
- Corresponding author
- Ettmayer, Peter
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-02-09
- Volume
- 62
- Issue
- 5
- Pages
- 2508-2520
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2913179893
- Cited by
- 138
- References
- 49
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 17 · 2023: 15 · 2022: 25 · 2021: 31 · 2020: 22 · 2019: 6
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- focal adhesion kinase, PROTACs, cereblon ligands, hepatocellular carcinoma, protein degradation, antiproliferative activity
- MeSH terms
- Humans, Ligands, Recombinant Proteins, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesion Kinase 1, Proteolysis
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