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Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth.

ABSTRACT: NEMO/IKKβ complex is a central regulator of NF-κB signaling pathway, its dissociation has been considered to be an attractive therapeutic target. Herein, using a combined strategy of molecular pharmacological phenotyping, proteomics and bioinformatics analysis, Shikonin (SHK) is identified as a potential inhibitor of the IKKβ/NEMO complex. It destabilizes IKKβ/NEMO complex with IC₅₀ of 174 nM, thereby significantly impairing the proliferation of colorectal cancer cells by suppressing the NF-κB pathway in vitro and in vivo. In addition, we also elucidated the potential target sites of SHK in the NEMO/IKKβ complex. Our study provides some new insights for the development of potent small-molecule PPI inhibitors.

SUBMITTER: Yu Z

PROVIDER: S-EPMC8904520 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth.

Yu Zhenlong Z Gao Jian J Zhang Xiaolei X Peng Yulin Y Wei Wenlong W Xu Jianrong J Li Zhenwei Z Wang Chao C Zhou Meirong M Tian Xiangge X Feng Lei L Huo Xiaokui X Liu Min M Ye Mingliang M Guo De-An DA Ma Xiaochi X

Signal transduction and targeted therapy 20220309 1

NEMO/IKKβ complex is a central regulator of NF-κB signaling pathway, its dissociation has been considered to be an attractive therapeutic target. Herein, using a combined strategy of molecular pharmacological phenotyping, proteomics and bioinformatics analysis, Shikonin (SHK) is identified as a potential inhibitor of the IKKβ/NEMO complex. It destabilizes IKKβ/NEMO complex with IC<sub>50</sub> of 174 nM, thereby significantly impairing the proliferation of colorectal cancer cells by suppressing ...[more]

PMID: 35260565

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