Identification of a Potent and Selective Focal Adhesion Kinase Proteolysis Targeting Chimera: Targeting Noncatalytic Functions of Focal Adhesion Kinase to Facilitate Antitumor Immunity

Focal adhesion kinase (FAK) has emerged as a promising
therapeutic
target since its pivotal involvement in tumorigenesis. However, FAK
inhibitors exhibit limited efficacy in suppressing FAK’s noncatalytic
functions, potentially compromising their therapeutic outcomes. Herein,
we developed a series of FAK PROTACs derived from our previously characterized
FAK inhibitor E10. Among them, compound D4 demonstrated a potent and selective FAK degradation effect, with
enhanced in vitro pharmacological activity relative
to E10, and upregulated antigen processing and presentation-related
genes. Further studies confirmed D4-mediated FAK degradation
augmented surface expression of major histocompatibility complex class
I (MHC-I) on tumor cells by repressing FAK kinase-independent function,
thereby enhancing tumor antigen presentation, facilitating the activation
of cytotoxic CD8+ T cells, and clearance of tumor cells in vivo. These findings indicate that pharmacological degradation
of FAK increases tumor immunogenicity through promoting antigen presentation
and confers enhanced therapeutic benefits compared to FAK inhibitors.