Focal Adhesion Kinase (FAK) is a key intracellular tyrosine kinase involved in cancer development, progression, and metastasis. FAK’s dual functions, both kinase-dependent catalytic activity and kinase-independent scaffolding, are critical in cancer processes. Current kinase inhibitors can only suppress its catalytic function, leaving its scaffolding role untouched. However, a novel approach using Proteolysis Targeting Chimeras (PROTACs) can degrade the FAK protein entirely, simultaneously inhibiting both functions. In this study, compound 16b, a newly developed PROTAC, was found to effectively degrade FAK in A549 cells with a DC50 of 6.16 ± 1.13 nM. It significantly inhibited cell proliferation, colony formation, migration, and invasion, surpassing the performance of the existing inhibitor, defactinib. Mechanistically, 16b functions through the CRBN-mediated ubiquitin-proteasome system, making it a promising candidate for future cancer therapies.
Wang, R.F. et al. / J. Chin. Pharm. Sci. 2024, 33 (9), 767–782.
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