| Structural highlights
Function
[KEAP1_MOUSE] Retains NFE2L2/NRF2 in the cytosol. Functions as substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1. Targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. May also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome (By similarity).[1] [2]
Publication Abstract from PubMed
KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct "hot-spots" for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery.,Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, Norton D, Rich SJ, Richardson C, Saxty G, Willems HM, Woolford AJ, Cottom JE, Kou JP, Yonchuk JG, Feldser HG, Sanchez Y, Foley JP, Bolognese BJ, Logan G, Podolin PL, Yan H, Callahan JF, Heightman TD, Kerns JK J Med Chem. 2016 Apr 28;59(8):3991-4006. doi: 10.1021/acs.jmedchem.6b00228. Epub , 2016 Apr 12. PMID:27031670[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999 Jan 1;13(1):76-86. PMID:9887101
- ↑ McMahon M, Itoh K, Yamamoto M, Hayes JD. Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003 Jun 13;278(24):21592-600. Epub 2003 Apr 7. PMID:12682069 doi:10.1074/jbc.M300931200
- ↑ Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, Norton D, Rich SJ, Richardson C, Saxty G, Willems HM, Woolford AJ, Cottom JE, Kou JP, Yonchuk JG, Feldser HG, Sanchez Y, Foley JP, Bolognese BJ, Logan G, Podolin PL, Yan H, Callahan JF, Heightman TD, Kerns JK. Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. J Med Chem. 2016 Apr 28;59(8):3991-4006. doi: 10.1021/acs.jmedchem.6b00228. Epub , 2016 Apr 12. PMID:27031670 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b00228
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