Sirtuin蛋白是一类烟酰胺腺嘌呤二核苷酸（NAD）依赖的去赖氨酸酰化酶，属于一种组蛋白去乙酰化酶，是近年来肿瘤治疗靶标的研究热点之一。目前已有5个组蛋白去乙酰化酶的小分子机理型抑制剂被FDA或CFDA批准上市，可见，机理型抑制剂的设计合成是开发该类靶向药物的有效策略。基于申请人前期对Sirtuin机理型抑制剂的研究基础，本项目以酰化赖氨酸为出发点，通过增加赖氨酸骨架的“柔性”或“刚性”，以及引入硫酰胺（thioamide）、甲酰胺基（carboxamido）或硫脲（thiourea）等导向Sirtuin的活性基团，进行全新设计合成一系列新型赖氨酸类似物，并开展体外和细胞水平的Sirtuin抑制活性、选择性以及后续抗肿瘤活性研究，考察其构效关系，以获得具有优异抑制活性和选择性的新型Sirtuin机理型抑制剂，为后续靶向药物研究与开发奠定基础。

Sirtuins, a class of enzymes known as nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, belong to histone deacetylase, which have been extensively studied as potential targets for anti-cancer therapy in recent years. Five small molecular inhibitors has been approved by FDA or CFDA, which are all mechanism-based inhibitors. Therefore, design and synthesis of small molecular mechanism-based inhibitors become a powerful strategy for the development of drug targeting histone deacetylase. Based on our previous experience in the development of Sirtuin mechanism-based inhibitors, this project will start from acyl lysine, consider the “flexibility” or “rigidity” of the backbone of lysine, and introducing inhibitory groups (“thioamide”, “carboxamido”, “thiourea”,etc) aiming Sirtuin to design and synthesize a series of novel lysine analogues. After in vitro and cellular study, these analogues will be evaluated for the inhibitory potency and selectivity for Sirtuin. We will further investigate their anti-tumor activity and the structure-activity relationship. Novel Sirtuin mechanism-based inhibitors with high potency and selectivity are expected to facilitate the research and development of novel drugs targeting Sirtuin.