Discovery and Development of Kelch-like ECH-Associated Protein 1. Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction Inhibitors: Achievements, Challenges, and Future Directions

Abstract

The transcription factor Nrf2 is the primary regulator of the cellular defense system, and enhancing Nrf2 activity has potential usages in various diseases, especially chronic age-related and inflammatory diseases. Recently, directly targeting Keap1-Nrf2 protein-protein interaction (PPI) has been an emerging strategy to selectively and effectively activate Nrf2. This Perspective summarizes the progress in the discovery and development of Keap1-Nrf2 PPI inhibitors, including the Keap1-Nrf2 regulatory mechanisms, biochemical techniques for inhibitor identification, and approaches for identifying peptide and small-molecule inhibitors, as well as discusses privileged structures and future directions for further development of Keap1-Nrf2 PPI inhibitors.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…The discovery of new peptides and small-molecule inhibitors of the KEAP1/NRF2 interaction has been reviewed recently (Abed et al, 2015;Jiang et al, 2016). Briefly, a series of truncated NRF2 peptides was initially evaluated as direct inhibitors of PPI using surface plasmon resonance and fluorescence polarization assays (Hu et al, 2013).…”

Identification of compounds that inhibit the binding of Keap1a/Keap1b Kelch DGR domain with Nrf2 ETGE/DLG motifs in zebrafish

“…48 This PPI is a major factor that regulates Nrf2 activity and offers ways to discover compounds that are potential Nrf2 activators by directly disrupting this interaction. 54 Ser49, Asn100, Arg101, Leu196 and Ser288 were the residues that formed the primary interactions with DGR domain of Keap1a, whereas Ser49, Ala53, Asn68, Asn100, Arg101, Arg169, Ser194, Val198 and Val292 contributed to the major part of the interaction with DGR domain of Keap1b. The identified top compounds interfered the binding of the Nrf2 with the Keap1a/Keap1b Kelch domain.…”

“…In case of zebrafish, two types of Keap1 proteins, Keap1a and Keap1b, form homodimers and heterodimers, thus interact with ETGE and DLG motifs of Nrf2 . This PPI is a major factor that regulates Nrf2 activity and offers ways to discover compounds that are potential Nrf2 activators by directly disrupting this interaction . Ser49, Asn100, Arg101, Leu196 and Ser288 were the residues that formed the primary interactions with DGR domain of Keap1a, whereas Ser49, Ala53, Asn68, Asn100, Arg101, Arg169, Ser194, Val198 and Val292 contributed to the major part of the interaction with DGR domain of Keap1b.…”

Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

“…[58][59][60] Z. Y. Jiang and his group developed a class of small-molecule inhibitors that target Keap1-Nrf2 PPI with nanomolar activities. [61][62][63][64][65] Besides, they also synthesized a Keap-dependent peptide PROTAC to knockdown Tau, 66 indicating that a new class of small-molecule PROTACs based on the Keap1 E3 ligase can be expected and its development is only just a matter of time.…”