基因组中富C序列可以折叠形成i-motif结构，在细胞内受到转录因子hnRNP K等调控，近期的核磁共振和抗体研究表明i-motif富集于启动子和端粒区域起关键调控作用，是潜在抗癌药物靶标。然而由于缺乏选择性配体，其调控基因转录功能研究结果矛盾，有的上调有的又下调癌基因的转录表达。我们在前期研究中合成筛选发现了选择性作用于i-motif的吖啶衍生物，可稳定c-myc启动子i-motif，下调c-myc转录表达。本项目将在此重要发现基础上，综合运用现代化学生物学技术，深入研究i-motif对多种癌基因的转录表达调控机制；探讨hnRNP K通过与i-motif相互作用调控癌基因转录表达分子机制；进一步合成筛选高选择性i-motif配体和hnRNP K抑制剂，为上述分子机制研究提供有力工具。本项目将为阐明i-motif与hnRNP K在癌基因转录表达调控中的作用和意义，为新型抗癌药物研究提供依据

In human genomics, C-rich sequences can form i-motif structures, which are regulated in cells by transcription factors including hnRNP K. Recent investigations with NMR and antibodies indicated that i-motif structures exist in cells located mainly at gene promoter and telomere regions, which play essential regulatory roles and are potential anticancer drug target. However, due to lack of selective binding ligand, their regulatory research results are contradictory, with some i-motif structures up-regulate while others down-regulate gene transcriptions. In our recent syntheses and screening, we found an acridine derivative, which could selectively bind and stabilize the i-motif at c-myc promoter and down-regulate its transcription and expression. Based on this important finding, we plan to carry out in-depth mechanistic studies for transcriptional regulation of various oncogenes by i-motif structures. We also plan to study the mechanism for hnRNP K to regulate oncogene transcription through its interaction with promoter i-motif. We will further synthesize and screen selective binding ligands for protein hnRNP K and oncogene promoter i-motifs as probes, providing powerful tools for the above mechanistic studies. This project will provide a new theoretical basis for elucidating function and significance of i-motif and hnRNP K in regulating oncogene transcription and expression, as well as discovery of new types of anti-cancer drugs.