Enzymatic inhibition has proven to be a successful modality for the development 
of many small-molecule drugs. In recent years, small-molecule-induced protein 
degradation has emerged as an orthogonal therapeutic strategy that has the 
potential to expand the druggable target space. Focal adhesion kinase (Fak) is a 
key player in tumor invasion and metastasis, acting simultaneously as a kinase 
and a scaffold for several signaling proteins. While previous efforts to 
modulate Fak activity were limited to kinase inhibitors with low success in 
clinical studies, protein degradation offers a possibility to simultaneously 
block Fak's kinase signaling and scaffolding capabilities. Here, we report the 
development of a selective and potent Fak degrader, PROTAC-3, which outperforms 
a clinical candidate, defactinib, with respect to Fak activation as well as 
Fak-mediated cell migration and invasion. These results underline the potential 
that PROTACs offer in expanding the druggable space and controlling protein 
functions that are not easily addressed by traditional small-molecule 
therapeutics.