Dong Ting, Li Chao, Wang Xing, Dian Longyang, Zhang Xiuguo, Li Lin, Chen She, Cao Ran, Li Li, Huang Niu, He Sudan, Lei Xiaoguang
Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
National Institute of Biological Sciences (NIBS), Beijing 102206, China.
Nat Commun. 2015 Mar 27;6:6522. doi: 10.1038/ncomms7522.
Aberrant activation of NF-κB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-κB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-κB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKα/β and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-κB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKα/β to block NF-κB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.
NF-κB的异常激活与癌症、自身免疫性疾病及炎症性疾病的发生发展相关。IKK作为NF-κB信号通路中公认的关键调节因子，是小分子抑制剂干预的理想靶点。在此，我们报道了一种复杂的天然产物——东风二聚体A是NF-κB信号通路的有效抑制剂。东风二聚体A选择性地结合IKKα/β保守的半胱氨酸46残基，并通过变构效应抑制其活性，从而抑制经典和非经典NF-κB信号通路。值得注意的是，东风二聚体A可诱导多种癌细胞死亡，抑制体内肿瘤生长以及内毒素介导的炎症反应。因此，东风二聚体A是一种靶向IKKα/β半胱氨酸46以阻断NF-κB信号传导的天然产物。故而，其在抗癌和抗炎治疗药物开发方面具有巨大潜力。
