Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation.

Focal adhesion kinase (FAK) is an intracellular tyrosine kinase that plays a critical role in the occurrence, development, and metastasis of cancer through both its kinase-dependent catalytic functions and kinase-independent scaffolding functions. Current kinase inhibitors target only its catalytic activity, leaving the scaffolding functions unaffected. However, proteolysis targeting chimeras (PROTACs) offers a promising approach by degrading the entire FAK protein, thereby inhibiting both functions simultaneously. In this study, we designed and synthesized novel PROTAC degraders, utilizing a defactinib derivative (compound 12) as the FAK ligand and a lenalidomide analog as the E3 ligase ligand. The structures of these compounds were confirmed through ¹H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). Among the synthesized compounds, the optimized compound 16b exhibited potent degradation activity against FAK protein in A549 cells, with a DC50 of 6.16 ± 1.13 nM, significantly inhibiting the proliferation and colony formation of these cells. Compared to defactinib, 16b showed enhanced inhibition of A549 cell migration and invasion. Furthermore, our research demonstrated that the rapid and effective FAK degradation induced by 16b was mediated by a CRBN-dependent proteasome mechanism. [ABSTRACT FROM AUTHOR]