开发PHD2小分子抑制剂来稳定HIF促进内源性EPO表达，已成为肾性贫血治疗药物的研究热点。然而HIF转录活性不仅受PHD2酶介导的Pro残基羟基化调控，还受FIH酶介导的Asn残基羟基化调控。鉴于此，本项目提出通过双重抑制PHD2/FIH酶活性协同作用的新策略。目前国内外尚未见PHD2/FIH双靶标抑制剂报道。本项目组前期在分析PHD2及FIH结合口袋共有特征基础上提出了“二齿螯合头部—连接链—芳环尾部”的双靶标抑制剂药效团模型。本项目拟运用靶标导向片段组装及原位活性筛选策略，来高效发现PHD2/FIH双靶标抑制剂先导物，兼顾“双靶标抑制活性、体内外药效学性质、药动学性质及安全性”进行成药性结构优化，以期获得具有PHD2/FIH双重抑制新机制、安全、口服有效的新型肾性贫血治疗候选药物。该研究有望拓展小分子肾性贫血治疗药物研究新领域；片段组装及原位筛选策略也可为其他靶向药物研究提供新思路。

That developing small-molecule inhibitors of prolyl hydroxylase domain 2 (PHD2) to stabilize the hypoxia inducible factor (HIF) and facilitate the expression of endogenous erythropoietin (EPO) has been a research hotspot in developing therapeutic drugs for the treatment of renal anemia. However, the transcriptional activity of HIF is not only modulated by PHD2-mediated enzymatic hydroxylation of Pro residues, but also modulated by factor inhibiting HIF (FIH)-mediated enzymatic hydroxylation of an Asn residue. Base on this, in this project we propose a new strategy for treating renal anemia in the light of the synergistic effects by dual inhibition of the enzymatic activities of both PHD2 and FIH. Up to now, none of the PHD2/FIH dual inhibitors has been reported worldwide. By analyzing the common features between the binding pockets of PHD2 and FIH, our research group has proposed a reasonable pharmacophore model for PHD2/FIH dual inhibitors that features with a bidentate chelating “head” fragment, an aromatic “tail” fragment, and a linker connecting the “head” and “tail”. In this project, we plan to efficiently discover PHD2/FIH dual inhibitors as lead compounds by utilizing target-directed fragment assembly and in situ screening strategy, and to carry out the druggable structural optimization with fully consideration of the dual inhibitory activities, in vitro and in vivo pharmacodynamic properties, pharmacokinetic properties, and safety profiles, in order to identify safe, orally active, and new drug candidates for treating renal anemia with a new mode of action by PHD2/FIH dual inhibition. This study has a promising potential for opening up a new research area for developing small-molecule drug for renal anemia therapy; the strategy combining fragment assembly and in situ screening is also prone to provide new ideas for the other target-based drug discovery.