法尼基转移酶及其抑制剂在肿瘤治疗中的研究进展  

Research progress of farnesyltransferase and its inhibitors in cancer therapy

作　　者：冯辰 胡清源 田铷 苏慧玲 安输[1] 徐天瑞[1] FENG Chen;HU Qing-yuan;TIAN Ru;SU Hui-ling;AN Shu;XU Tian-rui(Faculty of Life Science and Technology,Kunming University of Science and Technology,University Based Provincial Key Laboratory of Screening and Utilization of Targeted Drugs,Kunming 650500,China)

机构地区：[1]昆明理工大学生命科学与技术学院,云南省高校靶点药物筛选与利用重点实验室,云南昆明650500

出　　处：《中国药理学通报》2021年第8期1047-1053,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81760264,81960394);云南省基础研究计划重点项目(No 202001AS070024)。

摘　　要：法尼基转移酶(farnesyltransferase,FTase)是一种膜结合蛋白,其可通过对靶蛋白的法尼基化而实现对靶蛋白功能的调控。其中Ras蛋白是FTase最为重要的靶蛋白之一,这是因为大约三分之一的肿瘤存在Ras原癌基因突变。而因Ras蛋白独特的分子结构,致使其缺乏合适的药物分子结合口袋,并难以形成小分子化合物有效的作用靶点,所以对Ras蛋白功能具有重要调控作用的FTase逐渐成了研究焦点,许多FTase抑制剂(FTase inhibitors,FTIs)被研发并被应用于肿瘤的临床治疗,该文将简述FTase对Ras蛋白功能的调控及FTase对肿瘤发生发展的影响,重点综述近几年来FTase作为靶点的抗癌药物研究进展。Farnesyltransferase,a membrane-associated protein,catalyzes the addition of the 15-carbon fragment of farnesyl diphosphate to the cysteine SH group of the CAAX motif containing protein substrates to regulate the function of target proteins through farnesylation.As one of the most important target proteins of FTase,oncogenic forms of Ras mutants have been reportedly involved in more than 30%human cancers,and are known to play critical roles in cancer development and progression.Despite decades of research,Ras inhibitors are so elusive that no therapeutic agents directly targeting Ras mutants have been clinically approved,the primary reason for which is the lack of druggable pockets on the surface of Ras.Therefore,FTase,the main regulator of Ras protein,has gradually become a research hotspot,and many FTase inhibitors have been developed,synthesized and used for the treatment of malignant tumors.In the present review,we briefly describe the regulation of Ras functions by FTase and the role of FTase in cancers,and mainly explore the research progress of FTase inhibitors as a promising strategy for cancer therapy.

关 键 词：法尼基转移酶 法尼基转移酶抑制剂 RAS蛋白 肿瘤 MAPK信号通路 

分 类 号：R341[医药卫生—基础医学] R345.5