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Abstract: FR-PO474

Enarodustat (JTZ-951), an Oral HIF-PH Inhibitor, Stabilizes HIF-α Protein and Induces Erythropoiesis with Hardly Influence the Function of Vascular Endothelial Growth Factor

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Fukui, Kenji, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Shinozaki, Yuichi, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Kobayashi, Hatsue, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Deai, Katsuya, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Yoshiuchi, Hiromi, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Matsuo, Akira, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
  • Matsushita, Mutsuyoshi, Biological and Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan
Background

Renal anemia is principally caused by decreased erythropoietin (EPO) production in the kidney due to renal dysfunction. The production of EPO cannot be increased in response to hypoxia in the chronic kidney disease (CKD) kidney. The EPO production is regulated by hypoxia-inducible factor (HIF) -α, and it was hydroxylated by HIF-prolyl hydroxylase (PHD) and degradated by the ubiquitin-proteasome system. Several PHD inhibitors, including enarodustat are under clinical trials as treatment for renal anemia.

Methods

The enzyme inhibitory activity in human PHD enzymes was investigated by HTRF assay system. The expression of HIF proteins, EPO mRNA levels, and EPO proteins were evaluated by Western blotting, qPCR, and ELISA, respectively. Normal rats and 5/6-nephrectomized rats were used in in vivo experiment.

Results

Enarodustat had inhibitory effects on human PHD 1-3, but had no inhibitory effects on various receptors or enzymes. In Hep3B cells, enarodustat increased HIF-1α and HIF-2α protein levels, EPO mRNA levels, and EPO production. In normal rats, after a single oral dose of enarodustat, the plasma concentrations of enarodustat reached Cmax by one hour after administration, and then decreased rapidly. The liver and kidney EPO mRNA levels and plasma EPO concentrations also increased, and then both decreased by 24 hours. In 5/6-nephrectomized rats, repeated oral doses of enarodustat once daily showed the erythropoiesis stimulating effect in proportion to the doses from 1 mg/kg. The administration of enarodustat at the high dose (over 30 mg/kg) increased plasma vascular endothelial growth factor (VEGF), however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of enarodustat in the colorectal cancer cell-inoculated mice model. Although enarodustat dosing at the high dose increased the plasma VEGF, it showed no effect on the tumor growth.

Conclusion

Enarodustat stabilizes HIF-α protein and induces erythropoiesis with hardly influence the unexpected function, and it is expected to become a new orally drug that can maintain the hemoglobin concentrations in CKD patients with renal anemia.

Funding

  • Commercial Support