化学
核出口信号
药物发现
核蛋白
蛋白质-蛋白质相互作用
药物开发
结构生物学
生物化学
药品
药理学
转录因子
细胞核
生物
基因
作者
Cong Liu,Qian Zhou,Wei‐Ping Huang,Luyi Huang,Long Qin,Yuqin Lei,Da Jia,Shengyong Yang,Yang Yang,Xia Zhang,Qingxiang Sun
标识
DOI:10.1021/acs.jmedchem.3c01867
摘要
Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.
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