摘要
NF-κB是调节各种促存活基因表达的关键转录因子。IKK是激活NF-κB从细胞质转向细胞核与DNA结合至关重要的蛋白激酶。它是由三个亚基组成:IKKα、IKKβ、IKKγ(NEMO)。其中,IKKα和IKKβ是催化亚基,IKKγ是调节亚基。许多疾病,如霍奇金病、肝炎相关的肝细胞癌、结肠直肠癌、前列腺癌、类风湿性关节炎和炎性肠疾病,都与IKK和NF-κB有关。到目前为止,针对ATP结合位点的不同的IKK抑制剂已经通过高通量筛选、合理设计或通过计算机模拟的方法来鉴定。然而,只有其中三个(CHS-828、EB-1627和IMD-1041)已经在临床研究中,表明IKK抑制剂的设计策略需要调整。除了ATP竞争性抑制剂,其他几个抑制剂最近也已经公开并为IKK抑制剂的发现提供了一种新颖的概念。在这篇综述中,我们侧重于两部分:1)化学型与传统的ATP竞争性IKK抑制剂的结合模式;2)对作为NF-κB调节剂的非ATP竞争性的IKK抑制剂的鉴定新策略。通过这些讨论,我们希望为新的IKK抑制剂的开发提供建议。
关键词: ATP竞争性抑制剂,结合方式,IκB激酶(IKK),IKKβ抑制剂,NF-κB,蛋白质 - 蛋白质相互作用抑制剂,转录因子。
Current Medicinal Chemistry
Title:Recent Advances in the Structure-Based and Ligand-Based Design of IKKβ Inhibitors as Anti-inflammation and Anti-cancer Agents
Volume: 21 Issue: 34
Author(s): Jing-Jie Huang, Hong-Xi Chu, Zheng-Yu Jiang, Xiao-Jin Zhang, Hao-Peng Sun and Qi-Dong You
Affiliation:
关键词: ATP竞争性抑制剂,结合方式,IκB激酶(IKK),IKKβ抑制剂,NF-κB,蛋白质 - 蛋白质相互作用抑制剂,转录因子。
摘要: NF-κB is a significant transcription factor that regulates the expression of various pro-survival genes. IKK is a crucial protein kinase that activates NF-κB translocating from cytoplasm to nucleus for DNA binding. It is composed of three subunits, IKKα, IKKβ, IKKγ (NEMO), where IKKα and IKKβ are catalytic subunits, and IKKγ is the regulatory subunit. Many diseases, such as Hodgkin’s disease, Hepatitis-associated hepatocellular carcinoma, colorectal cancer, prostate cancer, rheumatoid arthritis and inflammatory bowel disease, are related to IKK and NF-κB. So far, various IKK inhibitors targeting the ATP binding site have been identified through high throughput screening, rational design or in silico methods, however, only three of them (CHS-828, EB-1627 and IMD-1041) have been under clinical studies, indicating the strategy for the design of IKK inhibitors need to be reinspected. Besides ATP-competitive inhibitors, several other inhibitors have also been disclosed recently, which provide novel concepts to the discovery of IKK inhibitors. In this review, we focus on two parts: 1) the chemotypes and binding patterns of the traditional ATP-competitive IKK inhibitors; 2) novel strategies for the identification of non-ATP-competitive IKK inhibitors as NF-κB modulators. Through these discussions we hope to present inspirations for the development of new IKK inhibitors.
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Huang Jing-Jie, Chu Hong-Xi, Jiang Zheng-Yu, Zhang Xiao-Jin, Sun Hao-Peng and You Qi-Dong, Recent Advances in the Structure-Based and Ligand-Based Design of IKKβ Inhibitors as Anti-inflammation and Anti-cancer Agents, Current Medicinal Chemistry 2014; 21 (34) . https://dx.doi.org/10.2174/0929867321666140815130205
DOI https://dx.doi.org/10.2174/0929867321666140815130205 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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