以癌基因重要转录调控组件为新靶点的药物化学研究

基于癌基因转录控制的抗癌策略是发展癌症分子靶向治疗药物的重要途径。癌基因启动子G-四链体与其结合蛋白协同作用所构成的调控组件，对控制癌基因转录至关重要。我们前期研究发现：NM23-H2蛋白可通过拆散癌基因G-四链体激活癌基因转录；特异性小分子能有效阻断该蛋白与癌基因G-四链体的组装，从而下调癌基因转录并抑制癌细胞增殖。据此，本项目提出了基于阻断G-四链体 / NM23-H2这一转录调控组件组装的抗癌新策略，拟在前期基础上应用药物化学等理论和技术，系统研究：NM23-H2与三种重要癌基因（C-MYC, KRAS和VEGF）G-四链体的相互作用及其生物学功能；靶向性新型小分子阻断剂的设计合成、筛选及化合物库构建；候选化合物发现及其抗癌机制、作用靶点及成药性。并由此揭示化学干预NM23-H2与G-四链体相互作用的内在规律和意义，为基于这一癌基因转录调控组件为新靶点的抗癌策略的可行性提供重要依据。

The anticancer strategy based on the transcriptional control of oncogene is an important way for developing molecular targeted cancer therapeutics. The transcriptional regulatory component formed by the interaction between oncogene promoter G-quadruplexes and their binding proteins is critical for the regulation of gene transcription. Our previous studies found that NM23-H2 protein could unwind G-quadruplex structures in a number of important oncogenes, and then activated gene transcription. In addition, specific small molecules could effectively block the interaction of the protein and G-quadruplex, down-regulate the transcription, and then inhibit the proliferation of cancer cell. In this research, we proposed a new anticancer strategy based on blocking the assembly of transcriptional regulatory component (NM23-H2/G-quadruplex as new target), and on the basis of the latest research results, we will apply theories and technologies of medicinal chemistry and so on to carry out the following researches: (1) investigation of interaction and biological function of NM23-H2/G-quadruplex of three important oncogene C-MYC, KRAS, and VEGF; (2) design and synthesis of novel small molecular ligands and construction of compound library; (3) screening of small molecular blocking agents and discovery of drug candidates; (4) studies on anticancer mechanism, target, and druggability of drug candidates. This project will reveal the inherent law and significance for the chemical interfering with the function of NM23-H2/G-quadruplex, and might provide an important theoretical and experimental basis for the feasibility of the anticancer research strategy based on the transcriptional control component of oncogene as new target.