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.
Anchoori
Ravi Kumar
RK
Division of Chemical Therapeutics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Harikumar
Kuzhuvelil B
KB
Batchu
Venkateswara Rao
VR
Aggarwal
Bharat B
BB
Khan
Saeed R
SR
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016328:NF-kappa B; D011753:Pyrones; D014409:Tumor Necrosis Factor-alpha; C548795:simplactone; D051550:I-kappa B Kinase