Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model

Abstract

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.

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

“…107 Encouragingly, the wide applications of different drug discovery strategies have allowed good Keap1 binding affinity to be achieved in a molecule containing only one or no acidic functionality. 96,109,119,121,129,134 Further structural optimization should concentrate on carefully balancing lipophilicity and polarity to enhance BBB permeability. Additionally, significant breakthroughs have been made in the field of structural biology.…”

“…Among the recently reported inhibitors, only compound 25 has been evaluated in the AD model, but the pharmacodynamic mechanism and pharmacokinetic profiles of 25 still need to be further explored . Encouragingly, the wide applications of different drug discovery strategies have allowed good Keap1 binding affinity to be achieved in a molecule containing only one or no acidic functionality. ,,,,, Further structural optimization should concentrate on carefully balancing lipophilicity and polarity to enhance BBB permeability. Additionally, significant breakthroughs have been made in the field of structural biology.…”

“…By performing a FP-based screening and optimizing the structure based on the SAR analysis, a strongly effective and orally available Keap1–Nrf2 inhibitor UBE-1099 ( 35 , Figure B) harboring the phenylpropanoic acid core was successfully discovered . Compound 35 could markedly inhibit the Keap1–Nrf2 PPI with an IC 50 value of 47.4 nM in the FP assay.…”

“…Notably, 35 could strongly induce Nrf2 activation and alleviate the dysfunction of the Nrf2-signaling pathway in the renal tissue of Alport mice. Moreover, the results of transcriptome analysis indicated that 35 could stimulate the expression of genes associated with the cell cytoskeleton and cycle in the glomeruli of Alport mice, which might contribute to its unique mechanism of CKD improvement …”

“…Moreover, the results of transcriptome analysis indicated that 35 could stimulate the expression of genes associated with the cell cytoskeleton and cycle in the glomeruli of Alport mice, which might contribute to its unique mechanism of CKD improvement. 119 Not long ago, another set of phenylpropanoic acid-based analogs was disclosed as Keap1−Nrf2 inhibitors that maintained great drug-like properties. 120 At the beginning of this research, a Biacore-based HTS of the in-house chemical library was conducted, resulting in the identification of a hit compound 36 (Figure 7A) with weak Keap1−Nrf2 inhibitory activity (Biacore: IC 50 = 40 μM) and favorable drug properties.…”