Reference | 1:Biochem Pharmacol. 2013 Dec 15;86(12):1775-83. doi: 10.1016/j.bcp.2013.09.017. Epub 2013 Sep 30. SC-514, a selective inhibitor of IKKβ attenuates RANKL-induced osteoclastogenesis and NF-κB activation.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, PMID: 24091016 DOI: 10.1016/j.bcp.2013.09.017 </br><span>Abstract:</span> The RANKL-induced NF-κB signaling pathway is essential for osteoclastogenesis. This study aims to identify specific inhibitors targeting NF-κB 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-κB activation in RAW264.7 cells as monitored by luciferase reporter gene assay, we identified SC-514, a specific inhibitor of IKKβ, as a candidate compound targeting osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis with an IC50 of <5μM. At high concentrations, SC-514 (≥12.5μM) induced apoptosis and caspase 3 activation in RAW264.7 cells. Moreover, SC-514 specifically suppressed NF-κB activity owing to delayed RANKL-induced degradation of IκBα and inhibition of p65 nuclear translocation. Taken together, our results indicate that SC-514 impairs RANKL-induced osteoclastogenesis and NF-κB activation. Thus, targeting IKKβ by SC-514 presents as a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss. Copyright © 2013 Elsevier Inc. All rights reserved.
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