Potential Applications of NRF2 Inhibitors in Cancer Therapy

Figure 1

NRF2 and KEAP1 structure/function relationship. (a) Schematic representation of the NRF2 structure from Homo sapiens. NRF2 is constituted by 7 highly conserved regions, referred to as Neh domains. From the N-term to the C-term, the Neh2 domain contains the DLG/ETGE motifs that are necessary for KEAP1-dependent NRF2 proteasomal degradation and several lysine residues that are directly ubiquitylated by the Cul3/Rbx1/E3 complex; also, a first NLS sequence is localized between the amino acids 42 and 53. The Neh4-5 domains mediate the interaction with Hdr1 and other proteins such as CBP and p300, activating NRF2-dependent transcription; also, NES (between amino acids 191-202) is localized in the Neh5 region. The Neh7 domain contains sites for RXR-α and RAR-α interaction that induces NRF2 transcriptional repression. The Neh6 domain contains two specific sites of interaction with the ubiquitin ligase βTrCP; the binding to the DSGIS motif requires the previous phosphorylation in S344 and S347 by Gsk-3β while in contrast, the interaction with the DSPAGS motif is direct. The Neh1 domain possesses the CNC bZIP region, required for DNA binding and dimerization with small MAF proteins and other transcription factors; also, a second NES sequence is localized between amino acids 553 and 562. Neh3 is another transactivation domain containing a second NLS sequence between amino acids 595 and 601. (b) Schematic representation of the KEAP1structure from Homo sapiens. KEAP1 is composed of 5 domains. The NTR (amino-term region) is followed by the BTB (broad complex, tram-track, and bric-à-brac domain), which is important for KEAP1 homodimerization and interaction with Cul3 and contains a redox-sensitive cysteine residue (Cys151). The next coming domain, known as IVR (intervening region), is a cysteine-rich motif that is particularly sensitive to redox changes and influences KEAP1 function. The next domain, known as DGR (double-glycine repeat), contains six Kelch motifs that promote protein-protein interactions with KEAP1 regulators including NRF2 and other functional partners. Lastly, the CTR (carboxy terminal region) is important for KEAP1-NRF2 interaction.

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