摘要
NEMO/IKKβcomplex 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/IKKβcomplex.Our study provides some new insights for the development of potent small-molecule PPI inhibitors.
基金
the National Natural Science Foundation of China(81930112 and 82004089)
National Key Research and Development Program of China(No.2018YFC1705900 and 2020YFE0202200)
Distinguished professor of Liaoning Province(XLYC2002008)
Dalian Science and Technology Leading Talents Project(2019RD15)for financial support.
