Focal adhesion tyrosine kinase (PTK2) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in many types of advanced-stage solid cancers. PTK2 has been shown to play an important role in adhesion, spreading, motility, invasion, metastasis, survival, angiogenesis, epithelial to mesenchymal transition (EMT), cancer stem cells and the tumor microenvironment^{2, 3}. Overexpression and activation of PTK2 is associated with several human malignant diseases, and is correlated with poor overall patient survival^4-6. The focal adhesion tyrosine kinase (PTK2) is often over-expressed in human hepatocellular carcinoma (HCC) and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity^{7, 8}. However, the clinical relevance of targeting PTK2 remains to be proven. Traditionally small molecules have been used to inhibit the action of a target protein by occupying and blocking a functional region of the protein. However, the disconnect between modulation of intracellular PTK2 autophosphorylation and growth inhibition as well as the often suboptimal selectivity profile of the inhibitors used makes it difficult to link the reported blockade of HCC tumour initiation and maintenance to PTK2 inhibition.

An alternative innovative approach is the development of proteolysis targeting chimeras (PROTACs), i.e. hetero bifunctional compounds consisting of one moiety that binds a Cullin RING E3 ubiquitin ligase linked to another that binds a desired protein of interest (POI), bringing the ligase and the POI into close spatial proximity  This hijacks the intrinsic catalytic activity of the E3 ligase and directs it toward the POI as a neo-substrate, triggering its poly-ubiquitination and subsequent proteasome-dependent degradation. As a result, a PROTAC acts as a degrader of the target as opposed to just an inhibitor, enabling the effective post-translational elimination of a target gene product in living organisms⁹. This approach presents many advantages compared to conventional target inhibition. One of the most attractive features of the approach is that a PROTAC molecule acts sub-stoichiometrically, i.e. it only needs to bind a molecule of target once to induce its degradation, and then is released and set free to bind another molecule of target and carry on, as in a catalytic cycle. For this reason, the concentrations required for PROTACs to be active in cells tend to be much lower compared to those needed to be reached and maintained with inhibitors, which can lead to fewer off-target effects and a more selective chemical intervention on the desired target.

Structure of BI-4464 (ligand in BI-0319) bound to PTK2 (PDB ID 6I8Z). Hydrogen bonds to cysteine 502 and aspartic acid 564 are depicted in blue.