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

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.