Characterization of a small-molecule inhibitor targeting NEMO/IKKβ to suppress colorectal cancer growth.
Zhenlong YuJian GaoXiaolei ZhangYulin PengWenlong WeiJianrong XuZhenwei LiChao WangMeirong ZhouXiangge TianLei FengXiaokui HuoMin LiuMingliang YeDe-An GuoXiaochi MaPublished in: Signal transduction and targeted therapy (2022)
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 50 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.
Keyphrases
- signaling pathway
- small molecule
- pi k akt
- protein protein
- oxidative stress
- bioinformatics analysis
- lps induced
- epithelial mesenchymal transition
- transcription factor
- photodynamic therapy
- induced apoptosis
- risk assessment
- nuclear factor
- inflammatory response
- anti inflammatory
- climate change
- toll like receptor
- endoplasmic reticulum stress