Novel Keap1-Nrf2 Protein-protein interaction inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome mouse model

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 chronic kidney disease (CKD). But the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods We developed a non-covalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on progressive phenotype in 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 lifespan of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in renal tissue of Alport mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Conclusions UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and presents a potential therapeutic drug for CKD.