Small-molecule antagonist targeting exportin-1 via rational structure-based discovery
Small-molecule antagonist targeting exportin-1 via rational structure-based discovery
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通过基于合理结构的发现靶向 Exportin-1 的小分子拮抗剂
DOI：
10.1021/acs.jmedchem.9b01663
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yongliang Yang
中科院分区：
文献类型：
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作者：
Xibao Tian;Jiali Gao;Meishuo Liu;Yuqin Lei;Fangjun Wang;Jin Chen;Peng Chu;Jiujiao gao;Feida Long;Minzhi Liang;Xiangyu Long;Huiying Chu;Cuixia Liu;Xueliang Li;Qingxiang Sun;Guohui Li;Yongliang Yang
Exportin-1（也被称为CRM1）在自身免疫性疾病中发挥着重要作用，并已成为结肠炎的潜在治疗靶点。在这里，我们报告了基于合理结构的export -1小分子拮抗剂LFS-829的发现，具有低范围纳摩尔活性。共晶结构、表面等离子体共振结合实验和基于细胞的表型核输出功能实验验证了export -1是LFS-829的关键靶点。此外，我们证明C528S突变或export -1的敲低可以使LFS-829的细胞活性丧失。引人注目的是，口服LFS-829可显著逆转结肠炎模型小鼠的病理特征。我们发现LFS-829可以通过靶向export -1在结肠炎小鼠中减弱NF-κB双信号通路和Nrf2细胞保护通路。此外，LFS-829具有极低的心脏毒性和急性毒性风险。因此，LFS-829在治疗结肠炎方面具有很大的前景，可能需要翻译用于临床试验。
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 cell-based 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-κB 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.