Signal Transduction and Targeted Therapy (Mar 2022)

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

  • Zhenlong Yu,
  • Jian Gao,
  • Xiaolei Zhang,
  • Yulin Peng,
  • Wenlong Wei,
  • Jianrong Xu,
  • Zhenwei Li,
  • Chao Wang,
  • Meirong Zhou,
  • Xiangge Tian,
  • Lei Feng,
  • Xiaokui Huo,
  • Min Liu,
  • Mingliang Ye,
  • De-an Guo,
  • Xiaochi Ma

DOI
https://doi.org/10.1038/s41392-022-00888-1
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

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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.