Small-Molecule Antagonist Targeting Exportin-1 via Rational Structure-Based Discovery

被引：20

作者：

Tian, Xibao ^{[4
]}

Gao, Jiali ^{[4
]}

Liu, Meishuo ^{[4
]}

Lei, Yuqin ^{[1
,2
]}

Wang, Fangjun ^{[5
,6
]}

Chen, Jin ^{[5
,6
]}

Chu, Peng ^{[4
]}

Gao, Jiujiao ^{[4
]}

Long, Feida ^{[4
]}

Liang, Minzhi ^{[4
]}

Long, Xiangyu ^{[4
]}

Chu, Huiying ^{[3
]}

Liu, Cuixia ^{[7
]}

Li, Xueliang ^{[7
]}

Sun, Qingxiang ^{[1
,2
]}

Li, Guohui ^{[3
]}

Yang, Yongliang ^{[4
]}

机构：

[1] Sichuan Univ, West China Hosp, Dept Pathol, Chengdu 610041, Peoples R China

[2] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China

[3] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Mol Modeling & Design, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China

[4] Dalian Univ Technol, Lab Innovat Drug Discovery, Sch Bioengn, Dalian 116023, Peoples R China

[5] Chinese Acad Sci, Natl Chromatog R&A Ctr, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Liaoning, Peoples R China

[6] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[7] Nanjing Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Nanjing 210029, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 08期

关键词：

NF-KAPPA-B; INTESTINAL EPITHELIAL-CELLS; INDUCED MOUSE MODELS; INCREASED SUSCEPTIBILITY; COLITIS; INFLAMMATION; INSIGHTS; DISEASE; IMMUNE; MICE;

D O I：

10.1021/acs.jmedchem.9b01663

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Exportin-1 (also named as CRM1) plays a prominent role in autoimmune disorders and has emerged as a potential therapeutic target for colitis. Here we report on the rational structure-based discovery of a small-molecule antagonist of exportin-1, LFS-829, with low-range nanomolar activities. The co-crystallographic structure, surface plasmon resonance binding assay, and cellbased phenotypic nuclear export functional assay validated that exportin-1 is a key target of LFS-829. Moreover, we demonstrated that the C528S mutation or the knockdown on exportin-1 can abolish the cellular activities of LFS-829. Strikingly, oral administration of LFS-829 can significantly reverse the pathological features of colitis model mice. We revealed that LFS-829 can attenuate dual NF-kappa B signaling and the Nrf2 cytoprotection pathway via targeting exportin-1 in colitis mice. Moreover, LFS-829 has a very low risk of cardiotoxicity and acute toxicity. Therefore, LFS-829 holds great promise for the treatment of colitis and may warrant translation for use in clinical trials.

引用

页码：3881 / 3895

页数：15

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