HDAC6和SIRT2都属于组蛋白去乙酰化酶家族，是许多疾病特别是恶性肿瘤的治疗靶标，而且它们共同调控的微管蛋白和K-RAS的乙酰化也与恶性肿瘤等相关疾病密切相关，所以，HDAC6和SIRT2双靶标抑制剂的设计合成作为抗肿瘤药物开发的一种新型靶向策略，具有非常重要的理论和现实意义。然而，目前为止还没有HDAC6和SIRT2双靶标抑制剂的报道，因此，本项目拟结合申请人有关SIRT2高选择性抑制剂的前期研究基础，通过双靶标药物分子设计策略，充分保留针对HDAC6与SIRT2的关键药效团，设计合成一系列连接型、融合型和并合型的候选分子，通过体外、细胞水平考查相关抑制活性、选择性和靶向性，最后对获得的双靶标抑制剂进行初步的抗肿瘤活性研究及再次的结构优化，以期获得若干基于HDAC6和SIRT2双靶标的抗肿瘤先导化合物，为后续的靶向药物研发奠定基础。

HDAC6 and SIRT2 all belong to this superfamily of histone deacetylase, which become hot therapeutic targets for many human diseases including cancer; moreover, they both can modulate tubulin and K-RAS acetylation, which is also associated with many human diseases including malignant tumor. Therefore, inhibitors that can both inhibit HDAC6 and SIRT2 as a novel stragety of development of anti-tumor drugs are desirable in physiological and pathological studies and may have further drug potential. However, up to date, there is no such dual inhibitor reported yet. To fill this blank, based on the previous research of highly selective SIRT2 inhibitors developed by the applicant, this project aims to design and synthesize candidate compounds for discovering dual inhibitors against HDAC6 and SIRT2. By using the strategy of dual target drug design, we will make full use of the key pharmacophores of several HDAC6 specific inhibitors and SIRT2 specific inhibitors to design and synthesize three types of candidate compounds: one is called “Connected type”; another is called “Fused type”; the last is called “Combined type”. With these candidate compounds in hand, we will investigate their inhibitory potency and selectivity for HDAC6 and SIRT2 by in vitro and in cells assay. In the meantime, we will also perform the binding assays for dual inhibitors with HDAC6 or SIRT2. Finally, we will perform the prelimerary anti-tumor study of the dual inhibitors and further optimize these inhibitors to obatain 1~2 dual inhibitors against HDAC6 and SIRT2 as lead compounds , which will facilitate the follow-up research and development of related target drugs.