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.