Cited by 146Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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

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Popow, Johannes, Arnhof, Heribert, Bader, Gerd, Berger, Helmut, Ciulli, Alessio, Covini, David, Dank, Christian, Gmaschitz, Teresa, Greb, Peter, Karolyi-Özguer, Jale, Koegl, Manfred, McConnell, Darryl B., Pearson, Mark, Rieger, Maria, Rinnenthal, Joerg, Roessler, Vanessa, Schrenk, Andreas, Spina, Markus, Steurer, Steffen, Trainor, Nicole, Traxler, Elisabeth, Wieshofer, Corinna, Zoephel, Andreas, Ettmayer, Peter·2019·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.8b01826

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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.

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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: Popow, Johannes
Bader, Gerd
Ciulli, Alessio
Dank, Christian
Greb, Peter
Koegl, Manfred
McConnell, Darryl B.
Pearson, Mark
Rinnenthal, Joerg
Trainor, Nicole
Wieshofer, Corinna
Zoephel, Andreas
Ettmayer, Peter
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
DOI: 10.1021/acs.jmedchem.8b01826
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: green
discovery.dundee.ac.uk
Licence: other-oa
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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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Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

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