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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Selective Small Molecule IB Kinase Inhibitor Blocks Nuclear Factor B-Mediated Inflammatory Responses in Human Fibroblast-Like Synoviocytes, Chondrocytes, and Mast Cells

Departments of Inflammation and Discovery Technologies, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

IB kinase (IKK) is essential for inflammatory cytokine-induced activation of nuclear factor B (NF-B). NF-B plays a pivotal role in the function of major cell types that contribute to the pathophysiological process of rheumatoid arthritis (RA). Here, we report the mechanism and the effect of the IKK inhibitor N-(6-chloro-7-methoxy-9H--carbolin-8-yl)-2-methylnicotinamide (ML120B), a -carboline derivative, on NF-B signaling and gene activation in RA-relevant cell systems. ML120B is a potent, selective, reversible, and ATP-competitive inhibitor of IKK with an IC₅₀ of 60 nM when evaluated in an IB kinase complex assay. ML120B does not inhibit other IKK isoforms or a panel of other kinases. ML120B concentration-dependently inhibits tumor necrosis factor (TNF)-stimulated NF-B signaling via inhibition of IB phosphorylation, degradation, and NF-B translocation into the nucleus. For the first time, we have demonstrated that in human fibroblast-like synoviocytes, TNF- or interleukin (IL)-1-induced monocyte chemoattractant protein-1 regulated on activation, normal T cell expressed and secreted and production is IKK-dependent. In addition, for the first time, we have demonstrated that lipopolysaccharide- or peptidoglycan-induced cytokine production in human cord blood-derived mast cells is IKK-dependent. In addition, in human chondrocytes, ML120B inhibited IL-1-induced matrix metalloproteinase production with an IC₅₀ of approximately 1 µM. ML120B also blocked IL-1-induced prostaglandin E₂ production. In summary, ML120B blocked numerous NF-B-regulated cell responses that are involved in inflammation and destructive processes in the RA joint. Our findings support the evaluation of IKK inhibitors as anti-inflammatory agents for the treatment of RA.

Address correspondence to: Danyi Wen, Inflammation Department, Millennium Pharmaceuticals, Inc., 35 Landsdowne Street, Cambridge, MA 02139. E-mail: wen{at}mpi.com

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