5.30588

IκB Ubiquitination Inhibitor, GS143

• Synonyme(s) : IκB Ubiquitination Inhibitor, GS143, 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
• Formule empirique (notation de Hill): C₂₈H₁₉FN₂O₄
• Numéro CAS: 916232-21-8
• Poids moléculaire : 466.46
• Code UNSPSC : 51111800
• ID de substance PubChem : 121513876
• Nomenclature NACRES : NA.77

Propriétés

• Pureté: ≥97% (HPLC)
• Niveau de qualité: 100
• Forme: powder
• Fabricant/nom de marque: Calbiochem^®
• Conditions de stockage: OK to freeze; protect from light
• Couleur: dark red
• Solubilité: DMSO: 25 mg/mL
• Température de stockage: 2-8°C
• Chaîne SMILES: C1=CC=C(C=C1)CC2=NN(C(=O)C2=CC3=CC=C(O3)C4=CC=CC=C4F)C5=CC=C(C=C5)C(=O)O

Description

Description générale

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 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 SCF^βTrCP1 from interacting with phosphorylated IκBα without inhibiting SCF^βTrCP1 E3 ligase activity directly, as no apparent accumulation of another known SCF^βTrCP1 substrate β-catenin is seen in HeLa S3 cells upon GS143 treatment (up to 20 µM for 3 h).

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 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). 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 NF-κB activation in lung tissue and airway inflammation in vivo. GS143 most likely prevents SCF^βTrCP1 from interacting with phosphorylated IκBα without inhibiting SCF^βTrCP1 E3 ligase activity directly.

Actions biochimiques/physiologiques

Cell permeable: yes

Primary Target
phosphorylated IκBα

Conditionnement

Packaged under inert gas

Avertissement

Toxicity: Standard Handling (A)

Reconstitution

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.

Autres remarques

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

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

Informations légales

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

Informations sur la sécurité

• Code de la classe de stockage: 11 - Combustible Solids
• Classe de danger pour l'eau (WGK): WGK 3
• Point d'éclair (°F): Not applicable
• Point d'éclair (°C): Not applicable