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

Abstract

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.

Keywords:

• FAK
• PROTACs
• PF-562271
• A549 cells
• protein degradation

Disclosure statement

No potential conflict of interest was reported by the author(s)

Additional information

Funding

We gratefully acknowledge the fnancial support from the Program for Innovative Research Team of the Ministry of Education and Programfor Liaoning Innovative Research Team in University.