SC-514, a selective inhibitor of IKK尾 attenuates RANKL-induced osteoclastogenesis and NF-魏B activation

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• 作者：Qian Liu ; Huafei Wu ; Shek Man Chim ; Lin Zhou ; Jinmin Zhao ; Haotian Feng ; Qingli Wei ; Qing Wang ; Ming H. Zheng ; Ren Xiang Tan ; Qiong Gu ; Jun Xu ; Nathan Pavlos ; Jennifer Tickner ; Jiake Xu
• 关键词：SC-514 ; Bone marrow cells ; Osteoclastogenesis ; RANKL ; NF-魏B
• 刊名：Biochemical Pharmacology
• 出版年：15 December, 2013
• 年：2013
• 卷：86
• 期：12
• 页码：1775-1783
• 全文大小：3104 K

文摘

The RANKL-induced NF-魏B signaling pathway is essential for osteoclastogenesis. This study aims to identify specific inhibitors targeting NF-魏B 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-魏B activation in RAW264.7 cells as monitored by luciferase reporter gene assay, we identified SC-514, a specific inhibitor of IKK尾, as a candidate compound targeting osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis with an IC50 of <5 渭M. At high concentrations, SC-514 (鈮?2.5 渭M) induced apoptosis and caspase 3 activation in RAW264.7 cells. Moreover, SC-514 specifically suppressed NF-魏B activity owing to delayed RANKL-induced degradation of I魏B伪 and inhibition of p65 nuclear translocation. Taken together, our results indicate that SC-514 impairs RANKL-induced osteoclastogenesis and NF-魏B activation. Thus, targeting IKK尾 by SC-514 presents as a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss.