过氧化物氧化还原酶1（PRDX1）是近年来发现的新型抗肿瘤药物靶标，已被确认为急性早幼粒细胞白血病（APL）等恶性肿瘤的有效靶标。然而现有的PRDX1抑制剂，活性、选择性、成药性都不够高，难以进入到临床试验阶段。本项目拟运用申请人自主开发的共价对接程序，及化合物结构改造程序，开展新型选择性PRDX1抑制剂的发现与优化研究，并解析新型PRDX1抑制剂的复合物晶体结构。在此基础上，本项目将通过与药物化学团队合作，获得活性与选择性更好的衍生物，并通过与药理学团队合作，开展新型PRDX1抑制剂在APL白血病PDX小鼠模型上的药效学评价研究。本项目的顺利开展和实现，一方面将为PRDX1相关的机制研究，提供化学探针质量的工具化合物，另一方面也将为APL白血病的临床治疗，提供有望成为候选药物的先导化合物。预计本项目将获得高成药性先导化合物1~2个，发表SCI论文2~3篇，申请专利1~2项。

Peroxiredoxin-1 (PRDX1) is a recently discovered new target for anti-tumor drugs, and was validated for the treatment of acute promyelocytic leukemia (APL) and other tumors. However, the potency, selectivity, and druggability of existing PRDX1 inhibitors are not satisfactory, and it is difficult for them to enter clinical trials. This project aims at the discovery and optimization of novel selective PRDX1 inhibitors, using the newly developed tools for covalent docking and compound structural optimization. Moreover, this project will try to solve the complex crystal structures of PRDX1 inhibitors. On this basis, this project will obtain derivative compounds with improved potency and selectivity, via cooperation with medicinal chemists. Then this project will systematically assess the efficacy of these novel PRDX1 inhibitors on the PDX mice model of APL, via cooperation with pharmacologists. Finally, this project will provide new lead compounds of candidate drugs, for the clinical treatment of APL, and also provide high-quality PRDX1 chemical probes, for related mechanism studies. This project expects to obtain 1~2 lead compounds with excellent druggability, publish 2~3 SCI papers, and submit 1~2 patents.