DDB1型
泛素连接酶
泛素
蛋白质降解
细胞生物学
药效团
化学
下调和上调
细胞周期蛋白依赖激酶
生物
生物化学
细胞周期
基因
作者
Lu Lv,Peihao Chen,Longzhi Cao,Yamei Li,Zhi Jiang Zeng,Yue Cui,Qingcui Wu,Jiaojiao Li,Jianhua Wang,Meng‐Qiu Dong,Xiangbing Qi,Ting Han
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2020-08-17
卷期号:9
被引量:117
摘要
Molecular-glue degraders mediate interactions between target proteins and components of the ubiquitin-proteasome system to cause selective protein degradation. Here, we report a new molecular glue HQ461 discovered by high-throughput screening. Using loss-of-function and gain-of-function genetic screening in human cancer cells followed by biochemical reconstitution, we show that HQ461 acts by promoting an interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and degradation of CDK12-interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of a CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that recruits its target protein directly to DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.
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