沃戈宁
化学
MG132型
小脑
蛋白酶体
蛋白酶体抑制剂
泛素
泛素连接酶
细胞生物学
黄芩
生物化学
生物
医学
基因
病理
中医药
替代医学
作者
Jinlei Bian,Jie Ren,Yongren Li,Jubo Wang,Xi Xu,Yifan Feng,Hui Tang,Yajing Wang,Zhiyu Li
标识
DOI:10.1016/j.bioorg.2018.08.028
摘要
Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a “click chemistry” approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level. Among these compounds, 11c could selectively degrade CDK9 in a concentration-dependent manner. In addition, the application of the proteasome inhibitor MG132 and CRBN siRNA silencing confirmed that 11c could promote the proteasome-dependent and CRBN-dependent degradation. Consistent with the degradation of the CDK9 protein, 11c selectively inhibits proliferation of CDK9-overexpressed cancer cells. Thus, our Wogonin-based PROTAC would be an efficient probe that induces the degradation of CDK9.
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