Structure-guided design of a potent focal adhesion kinase (FAK) degrader via ternary complex modeling and molecular dynamics simulation.

Focal adhesion kinase (FAK) functions as a critical regulator of integrin-mediated signaling, orchestrating tumor progression and metastasis via both kinase-dependent enzymatic activity and kinase-independent scaffolding functions. Herein, we report the identification of a potent FAK-targeting PROTAC 9c via structure-guided ternary complex modeling to optimize linker geometry. In MDA-MB-231 cells, 9c demonstrated subnanomolar FAK degradation potency (DC50 = 3.6 nM), outperforming its parental inhibitor in suppressing cell proliferation, colony formation, migration and invasion. Moreover, 9c synergized with cisplatin to enhance chemosensitivity. Mechanistic studies revealed that 9c induces FAK degradation via a VHL-dependent ubiquitin-proteasome pathway. Notably, molecular dynamics simulations confirmed the formation of a stable FAK-9c-VHL ternary complex, rationalizing the linker design strategy. Together, this study establishes a structure-guided PROTAC design paradigm for efficient linker optimization, with 9c serving as a promising lead compound for targeting FAK-driven malignancies.