癌基因c-MYC在多种癌细胞中均异常高表达，对癌症发生发展起关键作用。因c-MYC蛋白难靶向，c-MYC转录抑制是其抗癌药物研发的重要方向。c-MYC启动子核心调控序列NHE III1通过形成G-四链体结构抑制基因转录，是c-MYC转录调控重要的“沉默”元件，而癌细胞内大量存在的解旋酶DHX36能特异结合并解散该结构、重新激活转录。本项目通过前期构建的新评价方法，成功发现新型DHX36抑制剂D1能有效抑制DHX36解散G-四链体、下调c-MYC转录。据此，我们提出阻遏DHX36解散G-四链体以抑制c-MYC转录的抗癌新策略。本项目拟对D1进行结构改造，完善筛选评价体系，总结构效关系，以发现高选择性、高抑制力的新型c-MYC转录抑制剂；揭示其与DHX36的作用规律，探究其转录抑制及抗癌作用新机制；旨在发现新型抗癌先导化合物，为基于c-MYC转录抑制策略发展新型抗癌药物提供理论依据及实验支撑。

The oncogene c-MYC is abnormally highly expressed in various cancer cells and plays a key role in the development of cancer. Because c-MYC protein is difficult to target by small molecules, c-MYC transcriptional inhibition is an important direction for the development of its anticancer drugs. The c-MYC promoter core regulatory sequence NHE III1 inhibits gene transcription by forming a G-quadruplex structure, which is an important "silencing" element of c-MYC transcriptional regulation, and the large amount of helicase DHX36 in cancer cells can specifically bind and dissolve the structure and reactivate transcription. Through the new evaluation method constructed in the previous stage, this project successfully found the novel DHX36 inhibitor D1, which can effectively inhibit DHX36 from dissolving G-quadruplex and down-regulating c-MYC transcription. Accordingly, we propose a new anti-cancer strategy to suppress DHX36 disaggregation of G-quadruplex to inhibit c-MYC transcription. This project intends to carry out structural transformation of D1, improve the screening evaluation system, and the overall structure-effect relationship to discover new c-MYC transcriptional inhibitors with high selectivity and high inhibition; reveal their roles in interacting with DHX36, and explore their transcriptional inhibition and pharmacological mechanism for anticancer effects; aimed at discovering novel anticancer lead compounds, providing theoretical basis and experimental support for the development of novel anticancer drugs based on c-MYC transcriptional inhibition strategy.