新型p-21活化激酶4抑制剂的研发进展  

Research and development of novel p-21 activated kinase 4 inhibitors

作　　者：姚海梁 邓美岩 李馨阳 孟繁浩[1] YAO Hailiang;DENG Meiyan;LI Xinyang;MENG Fanhao(School of Pharmacy/Key Laboratory of Research and Development of Small Molecule Targeted Antitumor Drugs,China Medical University,Shenyang Liaoning 110122,China;Department of Thoracic Surgery,Shengjing Hospital of China Medical University,Shenyang Liaoning 110004,China;Department of Pharmacy,Shengjing Hospital of China Medical University,Shenyang Liaoning 110004,China)

机构地区：[1]中国医科大学药学院,小分子靶向抗肿瘤药物研究与开发重点实验室,辽宁沈阳110122 [2]中国医科大学盛京医院胸外科,辽宁沈阳110004 [3]中国医科大学盛京医院药学部,辽宁沈阳110004

出　　处：《中国药物警戒》2024年第7期822-828,共7页Chinese Journal of Pharmacovigilance

基　　金：国家自然科学基金资助项目(82104449)。

摘　　要：目的研究p-21活化激酶4(p21-activated kinase 4,PAK4)抑制剂在肿瘤治疗中的应用,为新型PAK4抑制剂的研发提供参考。方法从母核结构、共晶结构、药物活性、药代动力学、作用机制等方面,对小分子PAK4抑制剂进行论述。结果在多种PAK4抑制剂结构类型中,苯并呋喃类化合物KPT-9274对PAK4的抑制活性显著,对多种癌症具有抗肿瘤作用,是目前唯一处于临床试验阶段的PAK4抑制剂,可以作为今后PAK4抑制剂设计的基础。结论对苯并呋喃类化合物进一步结构优化,有望获得活性更优的PAK4抑制剂用于抗肿瘤研究。Objective To investigate the applications of p-21 activated kinase 4(PAK4)inhibitors in tumor therapy in order to provide reference for the development of novel PAK4 inhibitors.Methods Small molecule PAK4 inhibitors were elaborated in terms of structural scaffold,eutectic structure,activity and pharmacokinetics.Results Among various structures of PAK4 inhibitors,the benzofuran inhibitor KPT-9274 exhibited significant inhibitory effects and had antitumor effects on various cancers.It was currently the only PAK4 inhibitor in clinical trials and could facilitate future design of PAK4 inhibitors.Conclusion Optimization of the structure of benzofuran compounds is expected to lead to better PAK4 inhibitors for tumor treatment.

关 键 词：p-21活化激酶4 抑制剂 苯并呋喃 KPT-9274 靶向药物 肿瘤 

分 类 号：R979.1[医药卫生—药品]