靶向DNA Holliday junction结构新配体的发现及抗非BRCA突变型三阴性乳腺癌的机制研究

靶向DNA修复通路是三阴性乳腺癌（TNBC）药物研发的重要策略，但该策略在非BRCA突变型TNBC中效果不佳。因此，针对该类肿瘤的新靶点发现及化学干预研究意义重大。Holliday junction（HJ）是DNA修复中重要的核酸中间体，申请人前期发现一种新型HJ配体1a，其能够抑制DNA修复并选择性杀伤非BRCA突变型TNBC细胞，揭示了化学干预HJ是一种潜在的抗非BRCA突变型TNBC新策略。本项目拟以1a为先导化合物，设计、合成并筛选高选择性、高活性的新型HJ配体；通过相互作用研究解析化合物与HJ的结合模式并验证其胞内靶向性；结合蛋白组学及ChIP-seq技术阐明化合物作用HJ抑制DNA修复并杀伤非BRCA突变型TNBC的分子机制。本研究将明确HJ结构在TNBC进展中的分子调控网络，为基于HJ的TNBC靶向药物的研发提供理论依据。

DNA repair pathway is an important target on drug discovery for triple negative breast cancer (TNBC), but this strategy has been failing to achieve the desired effect in non-BRCA mutation TNBC. Therefore, it is of great significance to discovery a novel target and strategy in the treatment of non-BRCA mutation TNBC. Holliday junction (HJ) is an essential nucleic acid intermediate during DNA repair, and a newly discovered HJ ligand 1a has been found to be capable of inhibiting DNA repair and selectively killing non-BRCA mutation TNBC in our previous research. These findings suggested that HJ might be a potential target against non-BRCA mutation TNBC. On the basis of previous research, the project aims to accomplish the following goals:1) design, synthesize and screen to obtain a high activity leading compound. 2) identify the binding mode and cellular target. 3) reveal the molecular mechanism of leading compound in non-BRCA mutation TNBC using proteomic and ChIP-seq techniques. In conclusion, this project aims to illustrate the regulatory mechanism of HJ structures in TNBC progression and provide theoretical and experimental basis for the development of anti-TNBC drugs which target HJ structures.