Hypoxia-inducible factor (HIF) is identified to be a promising target to mediate the response to hypoxia. Its stability and activation are negatively controlled by prolyl hydroxylase 2 (PHD2). Thus, PHD2 inhibition has been perceived as a promising anti-anemia therapy. In this study, we carried out a structure-based virtual screening followed by in vitro and in vivo biological validation, with the goal to identify novel PHD2 inhibitors. As a result, a set of hits with new chemical scaffolds were revealed to be active in vitro for PHD2 inhibition. Compounds 2 and 3 were revealed to be capable of stabilizing HIF-α and stimulating erythropoietin (EPO) expression in cell-based assays. Notably, further in vivo assays revealed that 2 was capable of elevating the EPO plasma levels in C57BL/6 mice model. These findings provide new chemical scaffolds for further development of PHD2 inhibitors.

中文翻译：

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通过组合的虚拟筛选策略，发现具有新的化学骨架的脯氨酰羟化酶2抑制剂作为体内活性促红细胞生成素的诱导剂。

缺氧诱导因子（HIF）被确定为介导对缺氧反应的有希望的靶标。它的稳定性和激活受到脯氨酰羟化酶2（PHD2）的负面控制。因此，PHD2抑制已被认为是一种有前途的抗贫血疗法。在这项研究中，我们进行了基于结构的虚拟筛选，然后进行了体外和体内生物学验证，目的是鉴定新型PHD2抑制剂。结果，一组新的化学支架命中被证明在体外具有抑制PHD2的活性。在基于细胞的测定中，化合物2和3能够稳定HIF-α并刺激促红细胞生成素（EPO）的表达。值得注意的是，进一步的体内分析表明2能够提高C57BL / 6小鼠模型中EPO的血浆水平。