Inhibition of IkB kinase and NF-kappaB by a novel synthetic compound SK 2009.

The NF-kappaB family of transcription factors plays an important role in determining cell survival during immune, inflammatory, and stress responses. NF-kappaB activity is frequently deregulated in human cancers and is implicated in the resistance of tumor cells to diverse anticancer agents. We studied the effects of novel analogs of precursors of the natural product simplactone (A) on the activity of IkB kinase and NF-kappaB. Screening of six compounds for the ability to inhibit TNF-induced NF-kappaB activity revealed that compound SK2009 was the most potent of these compounds in suppressing NF-kappaB activation in KBM-5 leukemic cells. Further characterization of SK2009 indicates that this newly synthesized molecule can suppress TNF-induced IkappaBalpha kinase activation and inhibit the expression of three NF-kappaB-dependent gene products, cyclin D1, Bcl-2, and VEGF, in these cells. Published by Elsevier Ltd.