NF-κB normally exists in the cytoplasm of unstimulated cells as an inactive complex with a member of the IκB inhibitory protein family. This class of protein includes IκBα, IκBβ, and IκBε. IKK-1 and IKK-2 are two catalytic subunits of IκB kinase (IKK). BMS-345541 is a highly selective inhibitor of the catalytic subunits of IKK-2 and IKK-1 with IC50 of 0.3 μM and 4 μM, respectively[3]. In vitro, BMS-345541 at 0, 0.1, 1, and 10 μM treatment resulted in a concentration-dependent inhibition of melanoma cell (SK-MEL-5, A375, and Hs 294T) proliferation[4]. In vivo, BMS-345541 (0, 10, 25, and 75 mg/kg) was administered to melanoma tumor-bearing mice orally once daily for 21 days, and it was showed that BMS-345541 effectively inhibited SK-MEL-5 tumor growth in a dose-dependent manner[4]. BMS-345541 also dose-dependently inhibited the production of TNFα in the serum of animals challenged with an intraperitoneal administration of LPS. Approximately 50% inhibition was observed at 10 mg/kg, and dose of 100 mg/kg nearly completely inhibit serum TNFα[3].
作用机制
BMS-345541 binds to an allosteric site on IKK-2 and IKK-1.
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