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

靶向FAK的PROTACs的设计、合成及生物活性评价

作　　者：Ruifeng Wang Xin Zhao Hongbao Hou Ke Chen Shuihua Liu Ruyue Ren Yunfeng Liu Yi Zhang 王瑞峰;赵昕;侯宏保;陈珂;刘水华;任茹月;刘云峰;章毅(山西医科大学教育部慢性肾脏病医药基础研究创新中心,山西太原030001;山西医科大学基础医学院药理系,山西太原030001;山西医科大学第一医院内分泌科,山西太原030001;山西医科大学药学院,山西太原030001)

机构地区：[1]Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University,Taiyuan 030001,Shanxi,China [2]Department of Pharmacology,Shanxi Medical University,Taiyuan 030001,Shanxi,China [3]Department of Endocrinology,First Hospital of Shanxi Medical University,Shanxi Medical University,Taiyuan 030001,Shanxi,China [4]Department of Pharmacy,Shanxi Medical University,Taiyuan 030001,Shanxi,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2024年第9期767-782,共16页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.82204222,81973378 and 82073909);China Postdoctoral Science Foundation(Grant No.2022M722012);Shanxi Province Science Foundation for Youths(Grant No.20210302124191);Open Fund from Medicinal Basic Research Innovation Center of Chronic Kidney Disease,Ministry of Education,Shanxi Medical University(Grant No.CKD/SXMU-2024-02)。

摘　　要：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^(1)H NMR,^(13)C 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 DC_(50)of 6.16±1.13 n M,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.黏着斑激酶(FAK)是一种细胞内的酪氨酸激酶,具有激酶依赖的催化功能和激酶非依赖的支架功能,这两种功能在癌症的发生、发展、转移等过程中至关重要。目前的激酶抑制剂只能抑制其催化功能,而蛋白靶向降解嵌合体(PROTACs)可以将FAK蛋白降解来同时阻断两种功能。本研究设计合成了一类以defactinib衍生物化合物12为FAK蛋白的配体,来那度胺类似物为E3连接酶配体的新型PROTAC,其结构经核磁共振氢谱(^(1)H NMR)、核磁共振碳谱(^(13)C NMR)和高分辨质谱(HRMS)确证。其中,优选化合物16b对A549细胞中的FAK蛋白具有较强的降解活性(DC_(50)=6.16±1.13 nM),显著抑制A549细胞的增殖和克隆形成。与defactinib相比,16b显示出更强的抑制A549细胞迁移和侵袭活性。此外,研究表明16b通过CRBN介导的泛素蛋白酶体系统将FAK蛋白降解。

关 键 词：FAK PROTAC MIGRATION INVASION 

分 类 号：R916[医药卫生—药学]