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

Signal Transduct Target Ther. 2022 Mar 9;7(1):71. doi: 10.1038/s41392-022-00888-1.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Humans
  • I-kappa B Kinase* / genetics
  • I-kappa B Kinase* / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Serine-Threonine Kinases
  • Signal Transduction


  • NF-kappa B
  • Protein Serine-Threonine Kinases
  • I-kappa B Kinase