The I kappaB kinase (IKK) complex is involved in transcriptional activation by phosphorylating the inhibitory molecule I kappaB alpha, a modification that triggers its subsequent degradation, enabling activation of nuclear factor kappa B (NF-kappaB)[3]. IkappaB kinases (IKK) and IKK-related kinases play critical roles in regulating the immune response through nuclear factor-kappaB and IFN regulatory factor-dependent signaling transduction cascades[4].Diabetic rats exhibited significantly decreased levels of GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus and increased activation of the IKK/NF-κB/BACE1 pathway. Chronic ghrelin administration upregulated hippocampal PP1 expression, suppressed IKK/NF-κB/BACE1 mediated Aβ production, and improved cognition in STZ-induced diabetic rats[5]. SC-514 is a selective, orally active, ATP-competitive IKK-2 inhibitor (IC50=11.2±4.7 μM), obstructs NF-κB-dependent gene expression. SC-514 inhibits the native IKK complex or recombinant human IKK-1/IKK-2 heterodimer and IKK-2 homodimer similarly. IKK-2 inhibition by SC-514 is selective, reversible, and competitive with ATP. SC-514 inhibits transcription of NF-kappa B-dependent genes in IL-1 beta-induced rheumatoid arthritis-derived synovial fibroblasts in a dose-dependent manner.[6].SC514 also demonstrated ability to inhibit COX2 protein responses and a broad down-regulatory effect on uterine cell inflammatory gene expression[7].
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