Design, Synthesis and Biological Evaluation of FAK Degraders Based on a Rapid Assembly Strategy

To rapidly discover potent focal adhesion kinase (FAK)-targeted protein degraders and shorten the cycles of PROTAC synthesis and activity screening, a modular rapid assembly strategy was adopted in this work to efficiently construct two series (FM2-A and FM2-B) containing a total of 12 novel FAK degrader molecules in parallel. With DMSO set as the blank control and a known FAK degrader as the positive control, Western blot was utilized to systematically evaluate the FAK protein degradation activity of all compounds at the cellular level. The results revealed that FM2-A1–A3 and FM2-B1–B3 exhibited negligible target degradation capacity at 0.1 μM and 1 μM; FM2-A4–A6 and FM2-B4–B6 exerted concentration-dependent FAK degradation effects, among which FM2-A6 possessed the optimal degradation activity. At 1 μM, FM2-A6 displayed markedly higher target protein degradation efficiency than other derivatives in the same series, while its activity was inferior to that of the positive control. Structure activity relationship analysis demonstrated that rapid modular combination of linkers and warheads enables flexible regulation of the intracellular target clearance capacity of degraders. The integrated system combining modular rapid assembly and simultaneous activity screening established herein greatly improves the discovery efficiency of lead FAK degraders, and lays an efficient synthetic and screening foundation for the rapid development of PROTAC degraders targeting other kinase targets.