化学
小脑
表征(材料科学)
计算生物学
生物化学
纳米技术
基因
泛素
泛素连接酶
材料科学
生物
作者
Md Kabir,Lianju Qin,Kaixiu Luo,Yan Xiong,Rebecca A. Sidi,Kwang‐Su Park,Jian Jin
标识
DOI:10.1021/acs.jmedchem.4c00538
摘要
Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound 1 (MS181). We show that 1 induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner. Compound 1 also has superior antiproliferative activity in multiple metastatic cancer cell lines over EED-binding PRC2 degraders and can be efficacious in VHL-defective cancer cells. Altogether, compound 1 is a valuable chemical biology tool to study the role of PRC1 in cancer. Importantly, we show that CRBN can be utilized to develop bridged PROTACs, expanding the bridged PROTAC technology for degrading undruggable proteins.
科研通智能强力驱动
Strongly Powered by AbleSci AI