| 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
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 muM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 muM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.,Pallesen JS, Narayanan D, Tran KT, Solbak SMO, Marseglia G, Sorensen LME, Hoj LJ, Munafo F, Carmona RMC, Garcia AD, Desu HL, Brambilla R, Johansen TN, Popowicz GM, Sattler M, Gajhede M, Bach A J Med Chem. 2021 Apr 5. doi: 10.1021/acs.jmedchem.0c02094. PMID:33818106[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
- ↑ Pallesen JS, Narayanan D, Tran KT, Solbak SMO, Marseglia G, Sorensen LME, Hoj LJ, Munafo F, Carmona RMC, Garcia AD, Desu HL, Brambilla R, Johansen TN, Popowicz GM, Sattler M, Gajhede M, Bach A. Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds. J Med Chem. 2021 Apr 5. doi: 10.1021/acs.jmedchem.0c02094. PMID:33818106 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02094
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