Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors

作者全名："Li, Cong; Zhang, Qian; Huang, Wenxin; Huang, Luyi; Long, Qing; Lei, Yuqin; Jia, Da; Yang, Shengyong; Yang, Yang; Zhang, Xia; Sun, Qingxiang"

作者地址："[Li, Cong; Zhang, Qian; Huang, Wenxin; Huang, Luyi; Long, Qing; Lei, Yuqin; Yang, Shengyong; Zhang, Xia; Sun, Qingxiang] Sichuan Univ, West China Hosp, Dept Pathol, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Li, Cong; Zhang, Qian; Huang, Wenxin; Huang, Luyi; Long, Qing; Lei, Yuqin; Yang, Shengyong; Zhang, Xia; Sun, Qingxiang] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Li, Cong; Huang, Wenxin; Yang, Yang; Sun, Qingxiang] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Pulm & Crit Care Med, Chengdu 610032, Peoples R China; [Zhang, Qian] Sichuan Inst Edible Fungi, Chengdu 610066, Peoples R China; [Huang, Luyi] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ, Chongqing 400010, Peoples R China; [Jia, Da] Sichuan Univ, West China Univ Hosp 2, Key Lab Birth Defects Related Dis Women & Children, Dept Pediat,Div Neurol, Chengdu 610041, Peoples R China"

通信作者："Zhang, X; Sun, QX (通讯作者)，Sichuan Univ, West China Hosp, Dept Pathol, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Zhang, X; Sun, QX (通讯作者)，Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.; Sun, QX (通讯作者)，Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Pulm & Crit Care Med, Chengdu 610032, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:001134061700001

JCR分区：Q1

影响因子：7.3

年份：2023

卷号：66

期号：24

开始页：17044

结束页：17058

文献类型：Article

关键词：　

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."

基金机构："National Natural Science Foundation of China [82273850, 81803359]; National Natural Science Foundation of China [2022YFS0023]; Key Projects of Sichuan Province"

基金资助正文：This work was funded by the National Natural Science Foundation of China (NSFC #82273850 and 81803359) and Key Projects of Sichuan Province (2022YFS0023). The authors thank the staff from the BL17U1/BL18U/BL19U1 beamlines of Shanghai Synchrotron Radiation Facility (SSRF) for assistance during data collection.