The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β
The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β
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DOI：
10.1158/1535-7163.mct-06-0444
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发表时间：
2006-12-01
影响因子：
5.7
通讯作者：
Sporn, Michael B.
中科院分区：
文献类型：
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作者：
Yore, Mark M.;Liby, Karen T.;Sporn, Michael B.
合成的三萜1-[2-氰-3,12-二氧齐烷- 1,9(11)-二烯-28-酰基咪唑（CDDO-Im）是一种多功能药物，具有有效的抗炎、抗增殖、细胞保护和凋亡活性，其分子靶点尚不清楚。通过无细胞和细胞实验，我们发现CDDO-Im是IKK激酶的直接抑制剂，因此它抑制核因子κ B与DNA的结合和随后的转录激活。用CDDO-Im预处理细胞可阻止I κ B α磷酸化和对肿瘤坏死因子α的降解。CDDO- Im抑制的动力学是快速的，并在15分钟内发生。生物素化的CDDO-Im类似物表明，CDDO-Im与IKK信号体结合。此外，我们发现IKK上的Cys（179）是CDDO-Im的靶标。这是首次报道这种新型合成的三萜直接结合并抑制IKK。
The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1, 9(11)-dien-28-oyllimidazole (CDDO-Im) is a multifunctional agent with potent anti-inflammatory, antiproliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. Using both cell-free and cellular assays, we show that CDDO-Im is a direct inhibitor of I kappa B kinase (IKK) beta and that it thereby inhibits binding of nuclear factor-kappa B to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents I kappa B alpha phosphorylation and degradation in response to tumor necrosis factor alpha. The kinetics of this inhibition by CDDO- Im are rapid and occur within 15 min. A biotinylated analogue of CDDO-Im showed that CDDO-Im binds to the IKK signalsome. Furthermore, we show that Cys(179) on IKK is a target for CDDO-Im. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKK directly.