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Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy
Author(s) -
Yu Zhan,
Li Zhihong,
Yu Quanwei,
Wang Zhi,
Song Huilin,
Sun Hanyu,
Fan Rufeng,
Bi Angzhi,
Zhang Jun,
Zhang Xiaojin
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13640
Subject(s) - in vivo , erythropoietin , virtual screening , in vitro , chemistry , hypoxia (environmental) , hypoxia inducible factors , inducer , microbiology and biotechnology , biochemistry , drug discovery , pharmacology , biology , oxygen , gene , organic chemistry , endocrinology
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.