The Keap1-Nrf2-ARE signaling pathway acts to regulate transcription of a series of cytoprotective proteins (e.g. detoxifying and antioxidant defense enzymes and proteins) that protect cells from oxidative stress. This cytoprotective defense mechanism is a major contributor to the oxidative stress response, inflammation, and carcinogenesis, and pharmacological intervention in this pathway is being investigated as a strategy to discover novel therapeutics for cancer [3] and other oxidative stress-related diseases (e.g. neurodegenerative, cardiovascular, metabolic, and inflammatory diseases) [5-6].
One of the potentially useful strategies being investigated to produce small molecule Keap1-Nrf2-ARE pathway modulators, is the development of protein-protein interaction (PPI) inhibitors. For example, small molecules that inhibit the Keap1-Nrf2 PPI have been reported [1-2,4]. Note that inhibitors of the Keap1-Nrf2 PPI, act as functional Nrf2-ARE activators, as they release Nrf2 from inhibition allowing it to proceed to translocate to the nucleus and engage AREs to initiate protein expression.

1. Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ et al.. (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett, 23 (10): 3039-43. [PMID:23562243]

2. Jiang ZY, Xu LL, Lu MC, Chen ZY, Yuan ZW, Xu XL, Guo XK, Zhang XJ, Sun HP, You QD. (2015) Structure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction Inhibitor. J Med Chem, 58 (16): 6410-21. [PMID:26258437]

3. Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. (2017) The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep, 69 (3): 393-402. [PMID:28267640]

4. Lu MC, Ji JA, Jiang YL, Chen ZY, Yuan ZW, You QD, Jiang ZY. (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep, 6: 26585. [PMID:27215610]

5. Lu MC, Ji JA, Jiang ZY, You QD. (2016) The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Med Res Rev, 36 (5): 924-63. [PMID:27192495]

6. Magesh S, Chen Y, Hu L. (2012) Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev, 32 (4): 687-726. [PMID:22549716]