Kelch-like proteins: Introduction

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.

References

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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]

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Kelch-like proteins, introduction. Last modified on 27/02/2018. Accessed on 25/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=876.