Design, synthesis, and biological evaluation of potent FAK-degrading PROTACs

FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T (1/2) >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.

Automated summary

FAK regulates tumor cell migration, invasion, survival, proliferation, and tumor stem cell regulation through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. The development of FAK PROTACs has become a hot research topic, and the designed PROTAC A13 showed promising inhibitory activity against FAK kinase and protein degradation, as well as improved anti-proliferative and anti-invasion effects. These findings suggest that PROTAC A13 could be a useful tool for studying the functions of FAK and a potential therapeutic agent.