hit identification of ikkβ natural product inhibitor打击ikkβ自然产物抑制剂的识别.pdfVIP

Leung et al. BMC Pharmacology and Toxicology 2013, 14:3 /2050-6511/14/3 RESEARCH ARTICLE Open Access Hit identification of IKKβ natural product inhibitor 1* 2 3 3 2* Chung-Hang Leung , Daniel Shiu-Hin Chan , Ying-Wei Li , Wang-Fun Fong and Dik-Lung Ma Abstract Background: The nuclear factor- κB (NF-κB) proteins are a small group of heterodimeric transcription factors that play an important role in regulating the inflammatory, immune, and apoptotic responses. NF-κB activity is suppressed by association with the inhibitor IκB. Aberrant NF-κB signaling activity has been associated with the development of cancer, chronic inflammatory diseases and auto-immune diseases. The IKK protein complex is comprised of IKKα, IKKβ and NEMO subunits, with IKKβ thought to play the dominant role in modulating NF-κB activity. Therefore, the discovery of new IKKβ inhibitors may offer new therapeutic options for the treatment of cancer and inflammatory diseases. Results: A structure-based molecular docking approach has been employed to discover novel IKKβ inhibitors from a natural product library of over 90,000 compounds. Preliminary screening of the 12 highest-scoring compounds using a luciferase reporter assay identified 4 promising candidates for further biological study. Among these, the benzoic acid derivative (1) showed the most promising activity at inhibiting IKKβ phosphorylation and TNF-α- induced NF-κB signaling in vitro. Conclusions: In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKKβ inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKKβ phosphorylation activity in vitro, and block IκBα protein degradation and su