Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells  

作　　者：Peilu Song Fan Zhao Dahong Li Jiqiang Qu Miao Yao Yuan Su Hanxun Wang Miaomiao Zhou Yujie Wang Yinli Gao Feng Li Dongmei Zhao Fengjiao Zhang Yu Rao Mingyu Xia Haitao Li Jian Wang Maosheng Cheng 

机构地区：[1]Key Laboratory of Structure-Based Drug Design&Discovery of Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China [2]MOE Key Laboratory of Protein Sciences,School of Pharmaceutical Sciences,MOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical Biology,Tsinghua University,Beijing 100084,China [3]MOE Key Laboratory of Protein Sciences,Beijing Advanced Innovation Center for Structural Biology,Tsinghua-Peking Joint Center for Life Sciences,School of Life Sciences and School of Medicine,Tsinghua University,Beijing 100084,China [4]School of Traditional Chinese Materia Medica,Shenyang Pharmaceutical University,Shenyang 110016,China [5]School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shengyang 110016,China [6]Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [7]Department of Cell Biology,Key Laboratory of Cell Biology,Ministry of Public Health,and Key Laboratory of Medical Cell Biology,Ministry of Education,China Medical University,Shenyang 110001,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第6期2905-2922,共18页药学学报（英文版）

基　　金：supported by National Natural Science Foundation of China (Grant Nos.81230077,81872729 and 22077086);Overseas Expertise Introduction Project for Discipline Innovation (Grant No.D20029,China);Program for Innovative Talents of Higher Education of Liaoning (2012520005,China)。

摘　　要：The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substituted 6-ethynyl-1 H-indole derivatives that display high potential and specificity towards group Ⅱ PAKs.Among these inhibitors,compound 55 exhibited excellent inhibitory activity and kinase selectivity,displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16.Compound 55 exhibited potent in vivo antitumor metastatic efficacy,with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models,respectively.Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition(EMT).

关 键 词：ANTI-CANCER PAK4 inhibitor Kinase selectivity COCRYSTALLIZATION Lung metastasis EMT 

分 类 号：R914[医药卫生—药物化学]