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

doi:10.11938/cjmr20212928

摘要/Abstract

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.

关键词: 肿瘤基因, c-MYC, G-四链体(G4), 小分子药物, 核磁共振(NMR)

Abstract:

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.

Key words: tumor gene, c-MYC, G-quadruplex (G4), small molecular drug, nuclear magnetic resonance (NMR)

中图分类号:

O482.53

胡晓东,蓝文贤,王春喜,曹春阳. 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[J]. 波谱学杂志, 2021, 38(4): 503-513.

Xiao-dong HU,Wen-xian LAN,Chun-xi WANG,Chun-yang CAO. Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA[J]. Chinese Journal of Magnetic Resonance, 2021, 38(4): 503-513.

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