A novel FAK-degrading PROTAC molecule exhibited both anti-tumor activities and efficient MDR reversal effects  

作　　者：Ming-shi Xu Xiao-fan Gu Cong Li Li-xuan Pan Zi-xia Zhu Meng Fan Yun Zhao Jian-fang Chen Xuan Liu Xiong-wen Zhang 

机构地区：[1]Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai,200062,China [2]Nanjing Bestfluorodrug Pharmaceutical Technology Co.,Ltd,Nanjing,210023,China [3]Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai,201003,China [4]Key Laboratory of Chemistry of Plant Resources in Arid Regions,State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization,Xinjiang Technical Institute of Physics and Chemistry,Chinese Academy of Sciences,Urumqi,830011,China

出　　处：《Acta Pharmacologica Sinica》2024年第10期2174-2185,共12页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China(No.82373317,882374085 and 82303818);the Science and Technology Commission of Shanghai Municipality(20S11902200);the Natural Science Foundation of Shanghai(23ZR1460500);the China Postdoctoral Science Foundation(2023M731106);Xinjiang Uygur Autonomous Region’s Tianchi Talent-Professor Program.

摘　　要：FAK(focal adhesion kinase)is widely involved in cancer growth and drug resistance development.Thus,FAK inhibition has emerged as an effective strategy for tumor treatment both as a monotherapy or in combination with other treatments.But the current FAK inhibitors mainly concentrate on its kinase activity,overlooking the potential significance of FAK scaffold proteins.In this study we employed the PROTAC technology,and designed a novel PROTAC molecule F2 targeting FAK based on the FAK inhibitor IN10018.F2 exhibited potent inhibitory activities against 4T1,MDA-MB-231,MDA-MB-468 and MDA-MB-435 cells with IC_(50)values of 0.73,1.09,5.84 and 3.05μM,respectively.On the other hand,F2 also remarkably reversed the multidrug resistance(MDR)in HCT8/T,A549/T and MCF-7/ADR cells.Both the effects of F2 were stronger than the FAK inhibitor IN10018.To our knowledge,F2 was the first reported FAK-targeted PROTAC molecule exhibiting reversing effects on chemotherapeutic drug resistance,and its highest reversal fold could reach 158 times.The anti-tumor and MDR-reversing effects of F2 might be based on its inhibition on AKT(protein kinase B,PKB)and ERK(extracellular signal-regulated kinase)signaling pathways,as well as its impact on EMT(epithelial-mesenchymal transition).Furthermore,we found that F2 could reduce the protein level of P-gp in HCT8/T cells,thereby contributing to reverse drug resistance from another perspective.Our results will boost confidence in future research focusing on targeting FAK and encourage further investigation of PROTAC with potent in vivo effects.

关 键 词：FAK inhibitors PROTAC antitumor activity MDR reversal P-GP 

分 类 号：R979.1[医药卫生—药品]