SC-514

SC-514 is a cell-permeable and selective inhibitor of IKK-2 with IC50 value of 3-12μM [1, 2].

SC-514 inhibits all forms of recombinant human IKK-2 with IC50 values in the 3–12μM range. It also inhibits the native IKK complex. SC-514 specifically binds at the ATP-binding site of IKK-2 and exerts a reversible and competitive inhibition with ATP. However, SC-514 shows non-competitive inhibition with the IκB site. As an inhibitor of IKK-2, SC-514 is found to block the phosphorylation and degradation of IκBα and reduce the translocation level of p65 into the nucleus in IL-1β-treated RASFs. Additionally, SC-514 shows dose-dependent inhibition in the transcription of NF-κB-induced genes, including IL-6, IL-8, and COX-2. Moreover, SC-514 shows efficacious in reduction of LPS-induced TNFα production in the acute model of inflammation. SC-514 is also reported to inhibit the osteoclastogenesis in BMM cells through attenuating RANKL-induced activation of NF-κB [1, 2].

References:
[1] Kishore N, Sommers C, Mathialagan S, Guzova J, Yao M, Hauser S, Huynh K, Bonar S, Mielke C, Albee L, Weier R, Graneto M, Hanau C, Perry T, Tripp CS. A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. J Biol Chem. 2003 Aug 29;278(35):32861-71.
[2] Liu Q, Wu H, Chim SM, Zhou L, Zhao J, Feng H, Wei Q, Wang Q, Zheng MH, Tan RX, Gu Q, Xu J, Pavlos N, Tickner J, Xu J. SC-514, a selective inhibitor of IKKβ attenuates RANKL-induced osteoclastogenesis and NF-κB activation. Biochem Pharmacol. 2013 Dec 15;86(12):1775-83.

SC-514, a selective inhibitor of IKKbeta attenuates RANKL-induced osteoclastogenesis and NF-kappaB activation.[Pubmed:24091016]

Biochem Pharmacol. 2013 Dec 15;86(12):1775-83.

The RANKL-induced NF-kappaB signaling pathway is essential for osteoclastogenesis. This study aims to identify specific inhibitors targeting NF-kappaB signaling pathway, which might serve as useful small molecule inhibitors for the treatment and alleviation of osteoclast-mediated bone lytic diseases. By screening for compounds that selectively inhibit RANKL-induced NF-kappaB activation in RAW264.7 cells as monitored by luciferase reporter gene assay, we identified SC-514, a specific inhibitor of IKKbeta, as a candidate compound targeting osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis with an IC50 of <5muM. At high concentrations, SC-514 (>/=12.5muM) induced apoptosis and caspase 3 activation in RAW264.7 cells. Moreover, SC-514 specifically suppressed NF-kappaB activity owing to delayed RANKL-induced degradation of IkappaBalpha and inhibition of p65 nuclear translocation. Taken together, our results indicate that SC-514 impairs RANKL-induced osteoclastogenesis and NF-kappaB activation. Thus, targeting IKKbeta by SC-514 presents as a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss.

Selective inhibition of inhibitory kappa B kinase-beta abrogates induction of nitric oxide synthase in lipopolysaccharide-stimulated rat aortic smooth muscle cells.[Pubmed:15997236]

Br J Pharmacol. 2005 Sep;146(2):217-25.

In this study, we utilised a number of adenoviral constructs in order to examine the role of intermediates of the NF-kappaB pathway in the regulation of inducible nitric oxide synthase (iNOS) induction in rat aortic smooth muscle cells (RASMCs). Lipopolysaccharide (LPS) stimulated a significant increase in iNOS induction and NF-kappaB DNA binding. These parameters were substantially reduced by overexpression of a wild-type Ikappa-Balpha adenoviral construct (Ad.Ikappa-Balpha), confirming a role for NF-kappaB in iNOS induction. Infection with a dominant-negative IKKalpha adenoviral construct (Ad.IKKalpha+/-) did not significantly affect iNOS induction, NF-kappaB DNA binding or Ikappa-Balpha loss. Infection of RASMCs with adenovirus encoding a dominant-negative IKKbeta (Ad.IKKbeta+/-) essentially abolished iNOS induction and activation of the NF-kappaB pathway. Pretreatment of RASMCs with a novel specific inhibitor of IKKbeta, SC-514, significantly reduced iNOS induction, NF-kappaB DNA binding and I-kappaBalpha loss in a concentration-dependent manner. In both RASMCs and human umbilical vein endothelial cells (HUVECs), infection with Ad.IKKbeta+/- also inhibited COX-2 expression in response to LPS. However, Ad.IKKalpha+/- was again without effect. These data suggest that IKKbeta plays a predominant, selective role in the regulation of NF-kappaB-dependent induction of iNOS in RASMCs.

A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts.[Pubmed:12813046]

J Biol Chem. 2003 Aug 29;278(35):32861-71.

NF-kappa B-induced gene expression contributes significantly to the pathogenesis of inflammatory diseases such as arthritis. I kappa B kinase (IKK) is the converging point for the activation of NF-kappa B by a broad spectrum of inflammatory agonists and is thus a novel target for therapeutic intervention. We describe a small molecule, selective inhibitor of IKK-2, SC-514, which does not inhibit other IKK isoforms or other serine-threonine and tyrosine kinases. 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. When the mechanism of NF-kappa B activation was evaluated in the presence of this inhibitor, several interesting observations were found. First, SC-514 did not inhibit the phosphorylation and activation of the IKK complex. Second, there was a delay but not a complete blockade in I kappa B alpha phosphorylation and degradation; likewise there was a slightly slowed, decreased import of p65 into the nucleus and a faster export of p65 from the nucleus. Finally, both I kappa B alpha and p65 were comparable substrates for IKK-2, with similar Km and Kcat values, and SC-514 inhibited the phosphorylation of either substrate similarly. Thus, the effect of SC-514 on cytokine gene expression may be a combination of inhibiting I kappa B alpha phosphorylation/degradation, affecting NF-kappa B nuclear import/export as well as the phosphorylation and transactivation of p65.

SC-514 is a selective IKK-2 inhibitor (IC50=11.2 μM), which does not inhibit other IKK isoforms or other serine-threonine and tyrosine kinases.

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