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 . Among them, compound demonstrated a potent and selective FAK degradation effect, with enhanced pharmacological activity relative to , and upregulated antigen processing and presentation-related genes. Further studies confirmed -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 . These findings indicate that pharmacological degradation of FAK increases tumor immunogenicity through promoting antigen presentation and confers enhanced therapeutic benefits compared to FAK inhibitors.