Benzoxathiole derivative blocks lipopolysaccharide-induced nuclear factor-kappaB activation and nuclear factor-kappaB-regulated gene transcription through inactivating inhibitory kappaB kinase beta

Molecular Pharmacology
Byung Hak KimYoungsoo Kim

Abstract

Benzoxathiole derivatives have been used in the treatment of acne and have shown cytostatic, antipsoriatic, and antibacterial properties. However, little is known about the molecular basis for these pharmacological properties, although nuclear factor (NF)-kappaB activation is closely linked to inflammation and cell proliferation. Here, we demonstrate that the novel small-molecule benzoxathiole 6,6-dimethyl-2-(phenylimino)-6,7-dihydro-5H-benzo-[1,3]oxathiol-4-one (BOT-64) inhibits NF-kappaB activation with an IC(50) value of 1 muM by blocking inhibitory kappaB(IkappaB) kinase beta (IKKbeta), and suppresses NF-kappaB-regulated expression of inflammatory genes in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. BOT-64 inhibits IKKbeta-mediated IkappaBalpha phosphorylation in LPS-activated macrophages, resulting in sequential prevention of downstream events, including proteolytic degradation of IkappaBalpha, DNA binding ability, and transcriptional activity of NF-kappaB. BOT-64 inhibits LPS-inducible IKKbeta activity in the cells and catalytic activity of highly purified IKKbeta. Moreover, the effect of BOT-64 on cell-free IKKbeta was abolished by substitution of Ser-177 and Ser-181 residues in the activation loop of IKKbe...Continue Reading

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May 7, 2011·Archives of Pharmacal Research·Dong-Soon Im
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Mar 16, 2011·The Journal of Infectious Diseases·Eunmiri RohYoungsoo Kim
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Dec 22, 2020·European Journal of Immunology·Goutham VansarlaCaroline Bergenfelz

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