KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases. Considering the increasing interest of discovering novel NRF2 activators due to its clinical application, initial efforts were devoted to the development of electrophilic drugs able to induce NRF2 nuclear accumulation by targeting its natural repressor protein Kelch-like ECH-associated protein 1 (KEAP1) through covalent modifications on cysteine residues. However, off-target effects of these drugs prompted the development of an innovative strategy, the search of KEAP1-NRF2 protein-protein interaction (PPI) inhibitors. These innovative activators are proposed to target NRF2 in a more selective way, leading to potentially improved drugs with the application for a variety of diseases that are currently under investigation. In this review, we summarize known KEAP1-NRF2 PPI inhibitors to date and the bases of their design highlighting the most important features of their respective interactions. We also discuss the preclinical pharmacological properties described for the most promising compounds.

Keywords: KEAP1-NRF2 protein-protein interaction inhibitors; NRF2; NRF2-ARE pathway therapeutic potential; chronic diseases; phase II antioxidant response.

Figure 1

Molecular mechanisms of the KEAP1‐NRF2 ARE pathway showing the effect of direct protein–protein interaction inhibitors. ARE, antioxidant response element; BTB, bric‐a‐brac domain; CRL, cullin RING ligases; CUL3, cullin 3; IVR, intervening region; KEAP1, Kelch‐like ECH‐associated protein 1; NRF2, nuclear factor‐erythroid 2 p45‐related factor 2; RBX1, RING‐box protein 1; ROS, reactive oxygen species; sMAF, small musculoaponeurotic fibrosarcoma oncogene homologue; Ub, ubiquitin. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Structural basis of KEAP1‐NRF2 interaction. (A) Full model of CRL complex as previously described., NRF2 Neh2 domain structure is based on AlphaFold prediction. (B) Binding mode of NRF2 ETGE‐containing peptide (PDB‐ID 2FLU). (C) Binding mode of NRF2 DLG‐containing peptide (PDB‐ID 3WN7). BTB, bric‐a‐brac domain; Cul3, cullin 3; E2, ubiquitin‐conjugating enzyme E2; RBX1, RING‐box protein 1; UB, ubiquitin. Figure was generated with PyMol software. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

X‐ray crystallographic structures of KEAP1‐NRF2 ETGE and DLG truncated peptides (top row) and KEAP1 complexed with several compounds discussed in this review. Figure was generated with PyMol software. [Color figure can be viewed at wileyonlinelibrary.com]