HIF-1是肿瘤细胞适应缺氧环境的关键核转录调控因子，以HIF-1靶点的抗肿瘤药物有望克服肿瘤对放化疗的耐受，抑制肿瘤侵袭、转移。HIF-1α-ARNT异源二聚抑制剂具有靶点单一、特异性强的优点，但是目前结构稀缺。课题组前期发现LS-50为全新结构的HIF-1α-ARNT抑制剂，其活性和理化性质有待提升。本课题以LS-50为先导物，将经典药物设计与分子对接相结合，开展LS-50的针对性结构优化；同时采用分子对接方法，对化合物库进行虚拟筛选，获得全新骨架的HIF-1α-ARNT异源二聚抑制剂；在总结构效关系的基础上，优选高活性分子开展急性毒性、药动学和药效学评价，获得1-2个候选化合物用于抗肿瘤转移研究。另外，本研究有望获得HIF-1α-ARNT和HIF-2α-ARNT异源二聚的双重抑制剂及单一抑制剂，以其为特异性分子探针，探索HIF-1α和HIF-2α在缺氧肿瘤细胞中的生物学功能。

HIF-1 is the key nuclear transcription factor which regulate the tumor cells adaptation to hypoxia.The HIF-1 targeted antitumor agents have the potential to overcome tumor resistance to chemotherapy and prevent tumor invasion and metastasis. HIF-1α-ARNT heterodimerization inhibitors exhibited advantages with single target and specificity, while there is few structure of this series inhibitors been reported. Our previous work reveals compound LS-50 as novel structure HIF-1α-ARNT inhibitor, and its HIF-1 inhibitory activity and physico-chemical properties need to be improved. This project will combine the classic drug design and molecular docking together to carry out the targeted optimization of LS-50. Meanwhile, the molecular docking and virtual screening of compound libraries were performed to obtain novel skeletons of HIF-1α-ARNT heterodimerization inhibitors. On the basis of structure-activity relationship of all the compounds,highly potent compounds were chosen for the evaluations of acute toxicity, pharmacokinetics and pharmacodynamic to obtain 1-2 candidate compounds for anti-tumor metastasis research. In addition, the study is expected to get compounds as dual or single HIF-1α-ARNT and HIF-2α-ARNT heterodimerization inhibitor, which will be employed as specific molecular probes to explore the biological function of HIF-1α and HIF-2α in tumor hypoxia.