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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. K E Y W O R D Santi-anemia, EPO, HIF, PHD2 inhibitor, virtual screening SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section. How to cite this article: Yu Z, Li Z, Yu Q, et al. Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy. Chem Biol Drug Des. 2020;95:270-278.

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