泛素连接酶
平方毫米
蛋白质水解
泛素
DNA连接酶
核仁素
细胞生物学
连接器
生物
化学
计算生物学
生物化学
DNA
核心
基因
计算机科学
核仁
酶
操作系统
作者
Xuekun Fu,Jin Li,Xinxin Chen,Hongzhen Chen,Zhuqian Wang,Fang Qiu,Duoli Xie,Jie Huang,Siran Yue,Chunhao Cao,Yiying Liang,Aiping Lü,Chao Liang
标识
DOI:10.1016/j.chembiol.2024.03.011
摘要
Summary
Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.
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