6qmk | pdb_00006qmk
Small molecule inhibitor of the KEAP1-NRF2 protein-protein interaction
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 PubMedThe KEAP1/NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signalling during chronic oxidative stress may be associated with the pathophysiology of several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affinity for a cell-penetrant drug-like inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein-ligand interactions in three energetic "hot-spots" identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development, and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity. Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-associated protein 1 : Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction.,Heightman TD, Callahan J, Chiarparin E, Coyle JE, Griffiths-Jones CM, Lakdawala AS, McMenamin R, Mortenson PN, Norton D, Peakman T, Rich SJ, Richardson C, Rumsey WL, Sanchez Y, Saxty G, Willems H, Wolfe L, Woolford AJ, Wu Z, Yan H, Kerns JK, Davies TG J Med Chem. 2019 Apr 11. doi: 10.1021/acs.jmedchem.9b00279. PMID:30973731[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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