Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, 116000, China.
College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China.
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 IC 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.
NEMO/IKKβ 复合物是 NF-κB 信号通路的核心调节剂，其解离被认为是一个有吸引力的治疗靶点。在此，我们采用分子药理学表型分析、蛋白质组学和生物信息学分析相结合的策略，鉴定出紫草素（SHK）是 IKKβ/NEMO 复合物的潜在抑制剂。它以 174 nM 的 IC 破坏 IKKβ/NEMO 复合物，从而通过抑制 NF-κB 通路在体外和体内显著抑制结直肠癌细胞的增殖。此外，我们还阐明了 SHK 在 NEMO/IKKβ 复合物中的潜在靶位。我们的研究为开发有效的小分子 PPI 抑制剂提供了一些新的见解。
