Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent, Selective Small Molecule Inhibitor of IκB Kinase 2, TPCA-1 (2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation

Podolin, Patricia L.; Callahan, James F.; Bolognese, Brian; Li, Yue H.; Carlson, Karey; Davis, Talisha; Mellor, Geoff W.; Evans, Christopher A.; Roshak, Amy

doi:10.1124/jpet.104.074484

Cited by 271 publications

(220 citation statements)

References 37 publications

Supporting

Mentioning

209

Contrasting

Unclassified

Order By: Relevance

“…This is in concert with previous findings that TPCA-1 has higher inhibitory potency on either IKK-1 or IKK-2 than BMS-345541 Podolin et al, 2005). Both 10 μM BMS-345541 and 10 μM TPCA-1 exerted maximal inhibitory effects on the up-regulation of des-Arg 9 -bradykinin-and bradykinin -induced contraction, according to the inhibitory selectivity on IKK subtypes by BMS-345541 and TPCA-1, which suggests that both IKK-1 and IKK-2 subtype are involved in the transcriptional up-regulation of bradykinin B 1 and B 2 receptors.…”

Section: Discussionsupporting

confidence: 91%

“…Data obtained previously have demonstrated that NF-κB signaling plays an important role in the process up-regulation of the bradykinin B 1 receptor (Moreau et al, 2007;Ni et al, 1998;Sabourin et al, 2002;Schanstra et al, 1998). Others have also shown that the NF-κB pathway is important for inflammatory cytokine enhanced expression of bradyinin B 1 and B 2 receptors in osteoblasts and fibroblasts (Brechter et al, 2008) ; TPCA-1 is a highly selective IκB kinase 2 inhibitor, the results from 57 assays gave a mean IC 50 = 17.9 nM on IKK-2 and has 22-fold selectivity over IKK-1 (Podolin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

Lei

Zhang

Cao

et al. 2010

European Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

Lei

Zhang

Cao

et al. 2010

European Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

“…NF-B-DNA binding was significantly greater in human RA tissue compared with that from patients with osteoarthritis, and moreover, was localized to the sites of maximum tissue destruction (17). Increased NF-B-DNA binding activity has been demonstrated in synovial extracts from rats and mice following disease development (18,19). The inhibition of NF-B binding after IKK-2 inhibitor treatment has also been demonstrated in the mouse collagen-induced arthritis model (19) and the rat adjuvant-induced arthritis model (18).…”

Section: Discussionmentioning

confidence: 99%

“…Increased NF-B-DNA binding activity has been demonstrated in synovial extracts from rats and mice following disease development (18,19). The inhibition of NF-B binding after IKK-2 inhibitor treatment has also been demonstrated in the mouse collagen-induced arthritis model (19) and the rat adjuvant-induced arthritis model (18). In vivo imaging enabled us to visualize and quantify target activity in the inflamed joints of mice.…”

Section: Discussionmentioning

confidence: 99%

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Izmailova¹,

Paz²,

Alencar³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. The NF-B signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-B activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibodyinduced arthritis.Methods. ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-B activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.Results. Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-B activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-B pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor ␣, interleukin-1␤, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.Conclusion. Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.

show abstract

“…Interestingly, with the same LPS stimulation, the translocation of NF-κB/p65 from the cytoplasm to nucleus was significantly blocked by pretreatment with 10 μmol/L lobolide (as shown in Figure 5A-3a, 3b, 3c) and 5 μmol/L 2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1, Merck, USA) (as shown in Figure 5A-4a, 4b, 4c). TPCA-1 is an inhibitor of IKKα/β and selectively inhibits IKKβ 20-fold more than IKKα [18] . A final concentration of 0.1% (v/v) DMSO had no influence on LPS-stimulated NF-κB/p65 translocation to the nucleus, as reported previously (as shown in Figure 5A-5a, 5b, 5c) [19,20] .…”

Section: Lobolide Attenuated Nf-κb/p65 Nuclear Translocationmentioning

confidence: 99%

Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

Chen

et al. 2012

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Recent studies have shown that constitutive activation of the nuclear factor κB (NF-κB) plays a key role in chronic inflammation and cancers. The aim of this study was to characterize lobolide, a cembrane diterpene, as a drug candidate targeting the NF-κB signaling pathway. Methods: A HEK 293/NF-κB-Luc stable cell line was constructed to evaluate the effect of lobolide on NF-κB activation. THP-1 human monocytes and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were tested. Lipopolysaccharide (LPS)-induced TNFα and IL-1β production and activation of the TAK1-IKK-NF-κB pathway were studied using ELISA and Western blot analysis. Results: In HEK 293/NF-κB-Luc stable cells, lobolide (0.19-50 μmol/L) inhibited NF-κB activation in a concentration-dependent manner with an IC 50 value of 4.2±0.3 μmol/L. Treatment with lobolide (2.5-10 μmol/L) significantly suppressed LPS-induced production of TNFα and IL-1β in both THP-1 cells and PBMCs. In THP-1 cells, the suppression was partially caused by blockade of the translocation of NF-κB from the cytoplasm to the nucleus via affecting the TAK1-IKK-NF-κB pathway and p38 and ERK MAPK activity. Conclusion: Lobolide is a potential inhibitor of the NF-κB pathway, which blocks the translocation of NF-κB from the cytoplasm to the nucleus. Lobolide inhibits LPS-stimulated TNFα and IL-1β release, suggesting that the compound might be an anti-inflammatory compound.

show abstract

Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent, Selective Small Molecule Inhibitor of IκB Kinase 2, TPCA-1 (2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell Proliferation

Abstract: Demonstration that IB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-

Cited by 271 publications

References 37 publications

Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

Up-regulation of bradykinin receptors in rat bronchia via IκB kinase-mediated inflammatory signaling pathway

Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis

Lobolide, a diterpene, blockades the NF-κB pathway and p38 and ERK MAPK activity in macrophages in vitro

Contact Info

Product

Resources

About