哒嗪酮类新型HDAC与BRD4双重抑制剂的设计合成及生物活性研究

Histone deacetylases inhibitors (HDACI) has been always the important point of the anti-cancer drugs research. With the deep development of HDAC signal pathway and the clinical applications, the drug resistance and the limitation of HDACIs applications on solid tumor might be induced by recruitment of bromodomain protein (BRD4) In this program, a focused compounds library with pyridazinone as the druggable core structure were designed and synthesized based on the pharmacophore connections principle and hybridization strategy. Theses compounds, according to the previous SAR research of our novel HDACIs , were combined or hybridized with BRD4 pharmacophore groups and were made more structure optimizations under the bioactivity assay to find the lead compounds targeting both on the HDAC and BRD4. In a word, our program would resolve the drug resistance of HDACIs and BRD4 inhibitors in clinical trials, and meanwhile it would improve the applications of HDACI against solid tumor. Therefore, our program is meaningful and would lay a solid foundation for the applications of HDACI and BRD4 inhibitors in the discovery of novel anticancer drugs.

组蛋白去乙酰化酶抑制剂(HDACI)是抗肿瘤药物研究的重点。随着对其相关信号通路和临床应用的研究深入，发现其产生的耐药性和在实体瘤应用上的局限性，可能与BRD4蛋白相关。本项目是基于药效团拼接原理及药物分子杂交策略，以哒嗪酮为成药性母核，依据本课题组前期发现的新型HDACI的构效关系，将BRD4相关药效团和结构特征有机的结合，设计合成聚焦分子库，评价HDAC/BRD4生物活性，通过活性和成药性的结构优化，发现新型的双靶HDAC/BRD4的先导化合物及为相关生物学研究提供有价值的探针分子。本项目研究将为解决HDACI及BRD4抑制剂在临床上出现的耐药问题及提高HDACI在实体瘤上的应用具有重要意义，并为新型高效抗肿瘤药物的研究和应用奠定基础。

本项目基于药效团拼接原理及药物分子杂交策略，共设计、合成了117个、三种不同结构母核的化合物，包括三唑并哒嗪类BRD4-BD1选择性抑制剂（46个）、6-氮杂吲哚类的HDAC抑制剂（29个）和吡咯并吡啶酮类选择性HDAC与BRD4双靶抑制剂（42个）。其中，得到3个吡咯并吡啶酮类不同选择性HDAC/BRD4双靶抑制剂：41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4)和43d (HDAC6/BRD4(BD2))，并对其生物学效应做了对比评价，阐明了不同亚型选择性HDAC与BRD4双靶组合对细胞信号通路及凋亡影响的差异，为开发新型高效抗肿瘤药物奠定了生物学基础，该部分内容已发表SCI论文一篇，申请专利一项。