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
Abstract
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 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.