A novel FAK-targeted degrader: Design, synthesis, and therapeutic potential against colorectal cancer.

Focal adhesion kinase (FAK) is frequently overexpressed in colorectal cancer (CRC) and plays a pivotal role in tumor progression, making it an attractive therapeutic target. Although FAK inhibitors effectively suppress its kinase activity, they fail to block its non-enzymatic functions. Most reported FAK-targeting proteolysis targeting chimeras (PROTACs) have primarily focused on optimizing degradation efficiency, often with limited emphasis on the FAK warhead itself. Herein, a series of novel FAK-targeting PROTACs were designed and synthesized through systematic optimization of both the warhead moiety and linker composition.

Among these, compound 16 g emerged as the most potent degrader, exhibiting an IC50 value of 1.56 μM against HCT116 colorectal cancer cells while showing no cytotoxicity toward normal L02 cells. Western blot analysis confirmed that 16 g induced dose-dependent degradation of FAK protein in HCT116 cells.

Furthermore, 16 g significantly suppressed colony formation and demonstrated anti-angiogenic activity by inhibiting HUVEC cell proliferation.

These findings establish compound 16 g as a novel and potent FAK degrader with promising therapeutic potential for colorectal cancer.