Bardoxolone has been researched along with 1-(2-cyano-3-12-dioxooleana-1-9-dien-28-oyl)-imidazole* in 2 studies
2 other study(ies) available for Bardoxolone and 1-(2-cyano-3-12-dioxooleana-1-9-dien-28-oyl)-imidazole
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Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO.
The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface. Topics: Binding Sites; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; Models, Molecular; Molecular Conformation; Mutation; Oleanolic Acid; Protein Binding; Protein Interaction Domains and Motifs; Structure-Activity Relationship | 2014 |
Synthesis and biological evaluation of 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4-ethynylimidazole. A novel and highly potent anti-inflammatory and cytoprotective agent.
To explore more potent N-acylimidazole analogues of CDDO than CDDO-Im, which is one of the most potent compounds in several widely used bioassays related to protection against inflammation and carcinogenesis; we have synthesized and evaluated five new N-acyl(acetylenic)imidazole analogues. Among them, 4-ethynylimidazole 4 is nearly equivalent to CDDO-Im in potency in these bioassays. Remarkably, the solid form of 4 is more stable than that of CDDO-Im. These findings suggest that 4 is a very promising anti-inflammatory and cytoprotective agent and its further preclinical evaluation is warranted. Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Cytoprotection; Heme Oxygenase-1; Imidazoles; Interferon-gamma; Mice; NAD(P)H Dehydrogenase (Quinone); Nitric Oxide; Oleanolic Acid | 2011 |