Periodic, Partial Inhibition of IκB Kinase β-Mediated Signaling Yields Therapeutic Benefit in Preclinical Models of Rheumatoid Arthritis

Abstract

We have previously shown that inhibitors of IB kinase ␤ (IKK␤), including 4(2Ј-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKK␤ inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor ␣ production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKK␤ by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKK␤ by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T H 17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKK␤ is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKK␤ inhibitors.The multisubunit IB kinase (IKK) complex is essential in transducing the signal-inducible activation of the transcription factor NF-B in response to proinflammatory stimuli. In the "canonical" pathway of NF-B activation, the IKK complex catalyzes the phosphorylation of IB proteins at specific serine residues, which triggers a subsequent ubiquitination and proteolysis of IB, leaving NF-B free to translocate to the nucleus (Ghosh and Karin, 2002). This multisubunit IKK complex is composed of two catalytic subunits, termed IKK␣ and IKK␤, and a regulatory subunit termed NEMO (or IKK␥), which mediates upstream signals into activation of Article, publication date, and citation information can be found at

IκB kinase β Mediating the Downregulation of p53 and p21 by Lipopolysaccharide in Human Papillomavirus 16+ Cervical Cancer Cells

“…[222324] BMS-345541 exhibits an antitumor activity in a xenograft model of melanoma by inducing cell apoptosis[25] and sensitizes cancer cells to ionizing radiation or TRAIL. [2627] Although it is a relatively safe agent that does not cause significant normal tissue damage in vivo ,[2829] it remains to be determined the antitumor effects and safety of IKKβ inhibitors in the clinical trial.…”

Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care

“…BCR-stimulated human tonsillar B-cell proliferation: Human B cells from tonsils, isolated in media containing 10% FBS and various concentrations of BMS-986142, were stimulated with AffiniPure F(ab’)2 fragment goat anti-human IgG + IgM (Jackson ImmunoResearch) and incubated at 37°C for 72 hours [22]. The cells were then labeled with [ 3 H]-thymidine and incubated overnight at 37°C.…”

“…After 9 days in culture, cells were fixed and stained for tartrate-resistant acid phosphatase (TRAP; Sigma-Aldrich, St. Louis, MO, USA), and the number of TRAP-positive multinucleated cells (>2 nuclei per cell) was measured as described previously [22]. …”

2,8-Decadiene-1,10-Diol Inhibits Lipopolysaccharide-Induced Inflammatory Responses Through Inactivation of Mitogen-Activated Protein Kinase and Nuclear Factor-κB Signaling Pathway

“…Nuclear factor-κB (NF-κB), a key transcription factor for regulation of inflammation, controls the expression of pro-inflammatory proteins [7][8][9]. Excessive inflammatory responses by overexpression of proinflammatory proteins have been known to induce the occurrence and progression of chronic diseases including asthma, psoriasis, atherosclerosis, obesity, rheumatoid arthritis, inflammatory bowel disease, and cancer [10][11][12][13][14][15]. Therefore, NF-κB and intracellular signaling pathways responsible for production of pro-inflammatory proteins are widely appreciated as the therapeutic targets for inflammatory responses.…”