A selective small-molecule nuclear factor-kappaB inhibitor from a high-throughput cell-based assay for "activator protein-1 hits".
A selective small-molecule nuclear factor-kappaB inhibitor from a high-throughput cell-based assay for "activator protein-1 hits".
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DOI：
10.1158/1535-7163.mct-08-0811
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发表时间：
2009-03
影响因子：
5.7
通讯作者：
Colburn NH
中科院分区：
文献类型：
--
作者：
Kang MI;Henrich CJ;Bokesch HR;Gustafson KR;McMahon JB;Baker AR;Young MR;Colburn NH
NSC 676914已被鉴定为不抑制细胞增殖的选择性NF-κB抑制剂。该化合物最初是在使用合成化合物文库和NCI天然产物储存库的AP-1抑制剂的高通量基于细胞的测定中鉴定的。在荧光素酶报告基因试验中，NSC 676914在远低于AP-1的IC 50的浓度下显示出对NF-κB（核因子κ B）的活性。用作细胞增殖的特异性对照和指示剂的SRE（血清反应元件）报告物对化合物相对不敏感。NSC 676914预处理可抑制TPA诱导的IκB-α磷酸化和p65/50向细胞核的转位，但不能抑制p52从p100的加工，表明抑制NF-κB调节因子IKKβ而非IKKα。抑制NF-κB活化是阻断IKK磷酸化的结果。即使在1.1 µM的NSC 676914预处理下，TPA对IκB-α磷酸化的诱导也会减弱。相比之下，对于AP-1活化重要的激酶JNK和ERK 1和2没有显示出该化合物的显著抑制。此外，乳腺癌细胞系的基质胶侵袭试验和小鼠JB 6细胞中的转化试验表明，TPA诱导的侵袭和转化反应被该化合物完全抑制。这些结果表明，NSC 676914可能是一种新的抑制剂，具有潜在的治疗活性，靶向NF-κB用于癌症治疗或预防。
NSC 676914 has been identified as a selective NF-κB inhibitor that does not inhibit cell proliferation. This compound was originally identified in a high-throughput cell based assay for AP-1 inhibitors using synthetic compound libraries and the NCI natural product repository. NSC 676914 shows activity against NF-κB (Nuclear factor kappa B) in luciferase reporter assays at concentrations much less than the IC50 for AP-1. An SRE (Serum response element) reporter used as a specificity control and indicator of cell proliferation was relatively insensitive to the compound. Pretreatment with NSC 676914 is here shown to repress TPA-induced IκB-α phosphorylation and translocation of p65/50 to the nucleus, but not the processing of p52 from p100, suggesting inhibition of NF-κB regulator IKKβ rather than IKKα. Inhibition of NF-κB activation occurred as a consequence of blocking phosphorylation of IKK. Induction of IκB-α phosphorylation by TPA was diminished by pretreatment of NSC 676914 even at 1.1 µM. In contrast, kinases JNK and ERK1&2, important for AP-1 activation, showed no significant repression by this compound. Furthermore, a matrigel invasion assay with breast cancer cell lines and a transformation assay in mouse JB6 cells revealed that TPA-induced invasion and transformation responses were completely repressed by this compound. These results suggest that NSC 676914 could be a novel inhibitor having potential therapeutic activity to target NF-κB for cancer treatment or prevention.