IkappaB Ubiquitination Inhibitor, GS143 – Calbiochem

Descrição detalhada : A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCFβTrCP1-mediated ubiquitination of phosphorylated IκBα (IC50 = 5.2 µM), displaying little inhibitory potency against IKKβ-catalyzed IκBα phosphorylation, MDM2-mediated p53 ubiquitination, or the protease activities of cathepsin B, chymotrypsin, 20S & 26S proteasome (IC50 >100 microM). Effectively inhibits TNFα- and LPS-stimulated NF-κB transcription in HEK293, HT-29, and THP-1 cultures (IC50 from 2.1 to 10.5 microM). Intranasal administration (32 microg/20 microL/mouse) among OVA-sensitized mice 2 h prior to OVA challenge via inhalation greatly suppress NF-κB activation in lung tissue and airway inflammation in vivo. GS143 most likely prevents SCFβTrCP1 from interacting with phosphorylated IκBα without inhibiting SCFβTrCP1 E3 ligase activity directly., A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCFβTrCP1-mediated ubiquitination of phosphorylated IκBα (IC50 = 5.2 µM), displaying little inhibitory potency against IKKβ-catalyzed IκBα phosphorylation, MDM2-mediated p53 ubiquitination, or the protease activities of cathepsin B, chymotrypsin, 20S & 26S proteasome (IC50 >100 µM). Cellular IκBα degradation blockage by GS143 treatment (complete inhibition against TNFα-induced degradation with 30 min 20 µM drug pretreatment in in HeLa S3 and HT29 cultures) effectively inhibits TNFα- and LPS-stimulated NF-κB transcription in HEK293, HT-29, and THP-1 cultures (IC50 from 2.1 to 10.5 µM). Intranasal administration (32 µg/20 µL/mouse) among OVA-sensitized mice 2 h prior to OVA challenge via inhalation greatly suppress OVA challenge-induced NF-κB activation in lung tissue (>90% inhibition of nuclear NF-κB p65 DNA-binding activity 2 h post challenge) and airway inflammation (>80% reduction in eosinophils & lymphocytes in BALF 48 h post challenge) in vivo. GS143 most likely prevents SCFβTrCP1 from interacting with phosphorylated IκBα without inhibiting SCFβTrCP1 E3 ligase activity directly, as no apparent accumulation of another known SCFβTrCP1 substrate β-catenin is seen in HeLa S3 cells upon GS143 treatment (up to 20 µM for 3 h).
Sinónimos : IkappaB Ubiquitination Inhibitor, GS143 - Calbiochem; 4-(3-Benzyl-4-(5-(2-fluoro-phenyl)-furan-2-ylmethylene)-5-oxo-4,5-dihydropyrazol-1-yl)-benzoic acid, 4-(3-Benzyl-4-((5-(2-fluorophenyl)furan-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid, GS 143
Fórmula molecula r: C28H19FN2O4
Armazenamento : 2-8C; 2-8C; 2-8C
Embalagem : 1X1EA