IκB Ubiquitination Inhibitor, GS143-Calbiochem

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一般描述

A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCF^βTrCP1-mediated ubiquitination of phosphorylated IκBα (IC₅₀= 5.2 ?M), 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 ?M). Effectively inhibits TNFα- and LPS-stimulated NF-κB transcription in HEK293, HT-29, and THP-1 cultures (IC₅₀from 2.1 to 10.5 ?M). Intranasal administration (32 ?g/20 ?L/mouse) among OVA-sensitized mice 2 h prior to OVA challenge via inhalation greatly suppress NF-κB activation in lung tissue and airway inflammationin vivo. GS143 most likely prevents SCF^βTrCP1from interacting with phosphorylated IκBα without inhibiting SCF^βTrCP1E3 ligase activity directly.
A cell-permeable trisubstituted oxo-dihydropyrazolyl-benzoic acid that selectively inhibits the E3 ligase complex SCF^βTrCP1-mediated ubiquitination of phosphorylated IκBα (IC₅₀= 5.2 ?M), 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 ?M). Cellular IκBα degradation blockage by GS143 treatment (complete inhibition against TNFα-induced degradation with 30 min 20 ?M 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 (IC₅₀from 2.1 to 10.5 ?M). Intranasal administration (32 ?g/20 ?L/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 SCF^βTrCP1from interacting with phosphorylated IκBα without inhibiting SCF^βTrCP1E3 ligase activity directly, as no apparent accumulation of another known SCF^βTrCP1substrate β-catenin is seen in HeLa S3 cells upon GS143 treatment (up to 20 ?M for 3 h).

生化/生理作用

Cell permeable: yes
Primary Target
phosphorylated IκBα

包装

Packaged under inert gas

警告

Toxicity: Standard Handling (A)

重悬

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.
Use only fresh DMSO for reconstitution.

其他说明

Hirose, K., et al. 2008.Biochem. Biophys. Res. Commun.374,507.

Nakajima, H., et al. 2008.Biochem. Biophys. Res. Commun.368,1007.

法律信息

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

基本信息

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安全信息