靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展  

Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA

作　　者：胡晓东 蓝文贤[1] 王春喜 曹春阳[1] HU Xiao-dong;LAN Wen-xian;WANG Chun-xi;CAO Chun-yang(State Key Laboratory of Bioorganic and Natural Products Chemistry,Shanghai Institute of Organic Chemistry,Center for Excellence in Molecular Synthesis,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China)

机构地区：[1]中国科学院分子合成卓越中心,中国科学院上海有机化学研究所生命有机国家重点实验室,上海200032

出　　处：《波谱学杂志》2021年第4期503-513,共11页Chinese Journal of Magnetic Resonance

基　　金：国家重点研发计划资助项目(2017YFE0108200);国家自然科学基金资助项目(21977110,21778065,21807105);中国科学院先导项目(XDB20000000);中国科学院分子合成卓越中心资助项目(FZHCZY020600).

摘　　要：肿瘤基因MYC在人类70%癌细胞中高表达,抑制其转录是治疗肿瘤的有效手段.c-MYC启动子区P1近端的核酸酶超敏元件III1(NHE III1)控制MYC基因近90%的转录激活.NHE III1区域富含碱基G序列并且形成G-四链体(G4),调控c-MYC基因转录,是抗肿瘤药物靶标.但G4-DNA和G4-RNA的三维结构高度相似,小分子与其他G4(如端粒G4、mRNA G4、c-Kit G4等)的非特异性作用会产生小分子药物“脱靶”效应,同时小分子药物会诱导其他G4形成从而干扰正常细胞的功能,造成靶向c-MYC G4抗癌药物设计困难.本文综述了近些年靶向肿瘤因子c-MYC G4-DNA的小分子药物研究进展,及核磁共振(NMR)技术在G4-DNA和G4-RNA结构确定中的作用,为靶向c-MYC G4-DNA的小分子药物设计等相关研究工作提供参考.MYC is a highly expressed oncogene in about 70%of human cancer cells and inhibition of its transcription serves as an effective tumor treatment.The P1 proximal nuclease hypersensitive element(NHE)III1 of c-MYC promoter region controls nearly 90%transcriptional activation of MYC gene.This region enriched with base G forms G-quadruplex(G4)structure,which regulates c-MYC gene transcription and is a target of anti-tumor drugs.However,the three-dimensional structures of G4-DNA and G4-RNA are highly similar.Non-specific interactions between small molecules and other G4s,such as telomere G4,mRNA G4,c-Kit G4,etc.,yield“off-target”effects.Meanwhile,small molecules can induce the formation of other G4s,thus interfering with the function of normal cells.All of these hinder the design of anti-cancer drugs targeting c-MYC G4.In this paper,we summarize the recent research progress of small molecules targeting tumor factor c-MYC G4-DNA,and the role of nuclear magnetic resonance(NMR)in determining G4-DNA and G4-RNA structure.This review provides a reference for designing drugs targeting c-MYC G4-DNA and other related research works.

关 键 词：肿瘤基因 C-MYC G-四链体(G4) 小分子药物 核磁共振(NMR) 

分 类 号：O482.53[理学—固体物理]