Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model (Col4a5-G5X). Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change. Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD.
Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model (Col4a5-G5X). Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change. Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD.
Authors: Thomas G Davies; William E Wixted; Joseph E Coyle; Charlotte Griffiths-Jones; Keisha Hearn; Rachel McMenamin; David Norton; Sharna J Rich; Caroline Richardson; Gordon Saxty; Henriëtte M G Willems; Alison J-A Woolford; Joshua E Cottom; Jen-Pyng Kou; John G Yonchuk; Heidi G Feldser; Yolanda Sanchez; Joseph P Foley; Brian J Bolognese; Gregory Logan; Patricia L Podolin; Hongxing Yan; James F Callahan; Tom D Heightman; Jeffrey K Kerns Journal: J Med Chem Date: 2016-04-12 Impact factor: 7.446
Authors: Peter Rossing; Geoffrey A Block; Melanie P Chin; Angie Goldsberry; Hiddo J L Heerspink; Peter A McCullough; Colin J Meyer; David Packham; Pablo E Pergola; Bruce Spinowitz; Stuart M Sprague; David G Warnock; Glenn M Chertow Journal: Kidney Int Date: 2019-05-16 Impact factor: 10.612
Authors: Lauren E Tebay; Holly Robertson; Stephen T Durant; Steven R Vitale; Trevor M Penning; Albena T Dinkova-Kostova; John D Hayes Journal: Free Radic Biol Med Date: 2015-06-27 Impact factor: 7.376