Structural hybridization for inhibitors of the interaction between NRF2 and Keap1

Abstract

NRF2 is considered as a master regulator of cellular defense system under stressed conditions such as oxidative stress. In physiological conditions, NRF2 forms a complex with Keap1-Cul3 in the cytoplasm and undergoes ubiquitination and subsequent degradation. Under stressed conditions, the interaction between NRF2 and Keap1 is perturbed leading to NRF2 stabilization and migration to the nucleus where NRF2 activates genes accounting for antioxidative activities. Thus, small molecules that can disturb the interaction between NRF2 and Keap1 has been considered as promising for a variety of diseases. Herein, we report development of new, potent inhibitors of the interaction between NRF2 and Keap1 by deconvoluting previous inhibitors followed by structural hybridization. The most potent inhibitor identified by our FP assay showed IC50 of 0.6 mu M. We believe that our compounds will help to expand structural diversity of NRF2-Keap1 interaction inhibitors contributing to further development of promising candidates for various diseases.