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Hit identification of IKK? natural product inhibitor.

ABSTRACT: The nuclear factor-?B (NF-?B) proteins are a small group of heterodimeric transcription factors that play an important role in regulating the inflammatory, immune, and apoptotic responses. NF-?B activity is suppressed by association with the inhibitor I?B. Aberrant NF-?B signaling activity has been associated with the development of cancer, chronic inflammatory diseases and auto-immune diseases. The IKK protein complex is comprised of IKK?, IKK? and NEMO subunits, with IKK? thought to play the dominant role in modulating NF-?B activity. Therefore, the discovery of new IKK? inhibitors may offer new therapeutic options for the treatment of cancer and inflammatory diseases.A structure-based molecular docking approach has been employed to discover novel IKK? 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 IKK? phosphorylation and TNF-?-induced NF-?B signaling in vitro.In this study, we have successfully identified a benzoic acid derivative (1) as a novel IKK? inhibitor via high-throughput molecular docking. Compound 1 was able to inhibit IKK? phosphorylation activity in vitro, and block I?B? protein degradation and subsequent NF-?B activation in human cells. Further in silico optimization of the compound is currently being conducted in order to generate more potent analogues for biological tests.

SUBMITTER: Leung CH

PROVIDER: S-EPMC3583241 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Hit identification of IKKβ natural product inhibitor.

Leung Chung-Hang CH Chan Daniel Shiu-Hin DS Li Ying-Wei YW Fong Wang-Fun WF Ma Dik-Lung DL

BMC pharmacology & toxicology 20130107

<h4>Background</h4>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 th ...[more]

PMID: 23294515

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Project description:BackgroundThe development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet.MethodsThe somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression.ResultsHere, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade.ConclusionsThis is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.

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Hit identification of IKK? natural product inhibitor.

Publications

Hit identification of IKKβ natural product inhibitor.

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