JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor

Kenji Fukui, Yuichi Shinozaki, Hatsue Kobayashi, Katsuya Deai, Hiromi Yoshiuchi, Takuya Matsui, Akira Matsuo, Mutsuyoshi Matsushita, Tetsuhiro Tanaka, Masaomi Nangaku

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31 Citations (Scopus)

Abstract

JTZ-951 (enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1–3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.

Original languageEnglish
Article number172532
JournalEuropean Journal of Pharmacology
Volume859
DOIs
Publication statusPublished - 2019 Sept 15

Keywords

  • Erythropoietin
  • Hypoxia-inducible factor prolyl hydroxylase inhibitor
  • JTZ-951 (enarodustat)
  • Renal anemia
  • Vascular endothelial growth factor

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