A highly selective inhibitor of IκB kinase, BMS‐345541, blocks both joint inflammation and destruction in collagen‐induced arthritis in mice

Abstract

Objective. The transcription of several cytokines, cell adhesion molecules, and enzymes involved in the inflammatory and destructive mechanisms of rheumatoid arthritis is dependent on nuclear factor B (NF-B). Because IB kinase (IKK) is critical in transducing the signal-inducible activation of NF-B, we examined whether the highly selective and orally bioavailable IKK inhibitor BMS-345541 is efficacious against collagen-induced arthritis (CIA) in mice.Methods. Arthritis in DBA/1LacJ male mice was induced by subcutaneous immunization with bovine type II collagen on day 0 and day 21. BMS-345541 was administered perorally daily, either prophylactically (before disease onset) or therapeutically (after disease onset). Clinical assessment of the incidence and severity of disease was conducted throughout the study, and histologic evaluation was performed at the time of study termination (day 42).Results. When administered prophylactically, BMS-345541 (in a dose range of 10-100 mg/kg) was effective, in a dose-dependent manner, in reducing the incidence of disease and inhibiting clinical signs of disease. Histologic evaluation of the joints showed that both inflammation and joint destruction were blocked by the IKK inhibitor. Message levels of interleukin-1␤ in the joints were also dose-dependently inhibited in the mice that received BMS-345541. Dose-dependent efficacy in terms of both disease severity and histologic end points was observed with the therapeutic dosing regimen of BMS-345541, with use of the 100-mg/kg dose resulting in resolution of disease.Conclusion. IKK plays a key role in CIA in mice, and inhibitors of this enzyme represent a promising target for the development of novel agents to treat rheumatoid arthritis and other inflammatory diseases. BMS-345541 represents the first example of an inhibitor of IKK that has antiinflammatory activity in vivo.

Heparin Attenuates the Expression of TNFα-induced Cerebral Endothelial Cell Adhesion Molecule

“…In the present study, heparin inhibited NF-κB DNAbinding activity without affecting IκBα degradation or NF-κB nuclear translocation, suggesting that heparin activity occurs in the nucleus, rather than at other upstream levels of the NF-κB activating pathway, such as IκB kinase (McIntyre et al, 2003;Node et al, 1999) and proteasome (Meng et al, 1999;Read et al, 1995). Since heparin is a highly anionic glycosamninoglycan, that it is present in the nucleus of cerebral endothelial cells, and that the NF-κB DNA-binding domain consists largely of basic amino acids (Muller et al, 1995), it seems likely that heparin's anti-inflammatory properties lie in its ability to directly inhibit NF-κB DNA-binding activity (Lee et al, 2007).…”

Role of NF-κB in the skeleton

“…Many groups have demonstrated that inhibition of classical NF-κB, either genetically (deletion of IKKβ) or pharmacologically (NBD peptide, TAT-IκB-super repressor, IKKβ inhibitor), can ameliorate inflammation, and thus the subsequent bone erosion, in models of inflammatory arthritis [12,14,15,60,61]. Unfortunately, the resulting lack of inflammation prevents interpretation of in vivo results with respect to the role of NF-κB specifically in bone cells.…”

Regulation of c-Jun Phosphorylation by the IκB Kinase-ε Complex in Fibroblast-Like Synoviocytes

“…Understanding the critical signal transduction networks that modulate these host responses has stimulated the development of small molecule inhibitors as promising agents to treat RA (6 -8). For instance, NF-B blockade in RA has focused on the IB kinase (IKK) signal complex, which contains IKK2, as a key convergence point for rapid NF-B activation (9,10). However, systemic inhibition of IKK2 activity poses significant potential safety concerns due to the role of NF-B in host defense and apoptosis.…”