IκB Ubiquitination Inhibitor, GS143-Calbiochem

C₂₈H₁₉FN₂O₄

466.46

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.
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).

Cell permeable: yes
Primary Target
phosphorylated IκBα

Toxicity: Standard Handling (A)

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.

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

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

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

100

≥97% (HPLC)

powder

Calbiochem^®

OK to freeze
protect from light

dark red

DMSO: 25 mg/mL

2-8℃

Packaged under inert gas

11 - Combustible Solids

WGK 3