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Description

A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCF&beta,TrCP1-mediated ubiquitination of phosphorylated I&kappa,B&alpha, (IC50 = 5.2 µ,M), displaying little inhibitory potency against IKK&beta,-catalyzed I&kappa,B&alpha, phosphorylation, MDM2-mediated p53 ubiquitination, or the protease activities of cathepsin B, chymotrypsin, 20S & 26S proteasome (IC50 >100 microM). Effectively inhibits TNF&alpha,- and LPS-stimulated NF-&kappa,B 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-&kappa,B activation in lung tissue and airway inflammation in vivo. GS143 most likely prevents SCF&beta,TrCP1 from interacting with phosphorylated I&kappa,B&alpha, without inhibiting SCF&beta,TrCP1 E3 ligase activity directly., A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCF&,beta,TrCP1-mediated ubiquitination of phosphorylated I&,kappa,B&,alpha, (IC50 = 5.2 &,micro,M), displaying little inhibitory potency against IKK&,beta,-catalyzed I&,kappa,B&,alpha, phosphorylation, MDM2-mediated p53 ubiquitination, or the protease activities of cathepsin B, chymotrypsin, 20S &, 26S proteasome (IC50 >,100 µ,M). Cellular I&,kappa,B&,alpha, degradation blockage by GS143 treatment (complete inhibition against TNF&alpha,-induced degradation with 30 min 20 µ,M drug pretreatment in in HeLa S3 and HT29 cultures) effectively inhibits TNF&alpha,- and LPS-stimulated NF-&,kappa,B transcription in HEK293, HT-29, and THP-1 cultures (IC50 from 2.1 to 10.5 µ,M). Intranasal administration (32 µ,g/20 µ,L/mouse) among OVA-sensitized mice 2 h prior to OVA challenge via inhalation greatly suppress OVA challenge-induced NF-&,kappa,B activation in lung tissue (>,90% inhibition of nuclear NF-&,kappa,B 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 SCF&,beta,TrCP1 from interacting with phosphorylated I&,kappa,B&,alpha, without inhibiting SCF&,beta,TrCP1 E3 ligase activity directly, as no apparent accumulation of another known SCF&,beta,TrCP1 substrate &beta,-catenin is seen in HeLa S3 cells upon GS143 treatment (up to 20 µ,M for 3 h).