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Kidney Week

Abstract: PO1302

Novel Keap-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates the Severity of Experimental Alport Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Kaseda, Shota, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan
  • Suico, Mary Ann, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan
  • Ogi, Sayaka, Pharmaceuticals Research Laboratory, UBE Industries, Ube city, Yamaguchi, Japan
  • Sunamoto, Hidetoshi, Pharmaceuticals Research Laboratory, UBE Industries, Ube city, Yamaguchi, Japan
  • Fukiya, Hirohiko, Pharmaceuticals Research Laboratory, UBE Industries, Ube city, Yamaguchi, Japan
  • Nara, Futoshi, Pharmaceuticals Research Laboratory, UBE Industries, Ube city, Yamaguchi, Japan
  • Shuto, Tsuyoshi, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan
  • Onuma, Kazuhiro, Pharmaceuticals Research Laboratory, UBE Industries, Ube city, Yamaguchi, Japan
  • Kai, Hirofumi, Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan
Background

Bardoxolone methyl is an electrophilic agent that induces Nrf2 activation by irreversibly and covalently binding to the cysteine residue of Keap1. Bardoxolone methyl has been shown to improve glomerular filtration rate (GFR) in clinical trials, and is attracting attention as a novel agent for chronic kidney disease. However, there is concern about long-term efficacy due to the unknown mechanism of GFR improvement and transient increase in albuminuria. Moreover, irreversible Keap1 inhibitors such as Bardoxolone methyl may covalently bind to other proteins in a non-specific manner and induce side effects due to off-target activities.

Methods

We developed a reversible Keap1 inhibitor that inhibits Keap1-Nrf2 protein-protein interaction (PPI) and evaluated its efficacy using Alport syndrome mice model (Col4a5-G5X). Development of Keap1-Nrf2 PPI inhibitor was performed by fluorescence polarization and Nqo1 induction test. The obtained novel compound UBE-1099 (30 mg/kg/day) and CDDO-Im (3, 10 mg/kg/day; rodent tolerable Bardoxolone methyl analogue) were orally administrated to Alport mice and efficacy was evaluated.

Results

UBE-1099 showed higher Nqo1 induction efficiency compared with CDDO-Im in mouse renal tissue. While CDDO-Im only improved inflammation pathology in Alport mice, UBE-1099 uniformly improved renal function (GFR and Plasma creatinine, but not albuminuria), podocyte injury, glomerulosclerosis, inflammation and fibrosis. Moreover, UBE-1099 treatment significantly prolonged the lifespan of Alport mice.

Conclusion

This study firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis. We will elucidate next the mechanism of renal pathology improvement, which may provide useful information for Nrf2 activators including bardoxolone methyl for clinical application.

Funding

  • Other NIH Support