PI3K和HDAC6是近年来抗肿瘤靶向药物研究的热门靶点，单个靶点抑制剂存在对实体瘤效果不佳、毒副作用大等缺点。联用该两个靶点的抑制剂能够达到协同增效的实体瘤抑制效果。同时，实现对HDAC6的选择性，能够避免不必要的毒副作用。基于此，本项目通过构建具有PI3K抑制活性骨架与锌离子结合侧链的虚拟化合物库，经过对接筛选，设计出一类具有PI3K/HDAC6双重抑制活性的小分子化合物，并进行化学合成。对所合成的目标产物进行体外和体内的分子、细胞及动物水平的抗肿瘤活性及成药性筛选，优选出新药开发的候选苗子化合物。预实验中已合成具有纳摩尔级抑酶活性的PI3K/HDAC6抑制剂，并对多种实体瘤细胞有优异的抗增殖活性。该项目首次开展PI3K/HDAC6双靶点的抑制剂研究，对实体瘤有增效减毒的靶向作用，为实体瘤药物治疗提供新的研究思路，有望为小分子靶向抗肿瘤药物研究领域开辟一个新的方向。

PI3K and HDAC6 are popular targets in the field of antitumor drugs. The poor effectiveness to solid tumors and side effects are main shortcomings of single target inhibitors. Combinations of PI3K and HDAC6 inhibitors increased anti-tumor activities compared to each single treatment in a synergistic manner. And selectivity from other HDAC isoforms avoids some side effects. Based on this, this project aims to design and synthesis of PI3K/HDAC6 dual small molecular inhibitors through building a virtual compound library of scaffold with bioactivity and zinc-binding side chains, screening based on molecular docking. The synthesized compounds are examined on enzymatic and cellular inhibition in vitro, and antitumor activities in vivo. The compoounds are filtered with druggability, leading to candidate discovery of new drug development. In preliminary experiment, dual PI3K/HDAC6 inhibitors were synthesized. These compounds displayed inhibition on enzyme in nanomole concentration, and exhibited excellent anti-proliferation activities against solid tumor cells. This first research on PI3K/HDAC6 dual inhibitors provides a new approach to drug therapy for solid tumors. This project aims to enhance the antitumor effectiveness and lower side effects on solid tumors, which offers a new research direction on small molecular targeted drugs with solid tumor inhibition.