Small-Molecule Antagonist Targeting Exportin-1 via Rational Structure-Based Discovery.
Xibao TianJiali GaoMeishuo LiuYuqin LeiFang-Jun WangJin ChenPeng ChuJiujiao GaoFeida LongMinzhi LiangXiangyu LongHuiying ChuCuixia LiuXueliang LiQingxiang SunGuo-Hui LiYongliang YangPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- small molecule
- high throughput
- protein protein
- clinical trial
- oxidative stress
- ulcerative colitis
- high fat diet induced
- signaling pathway
- cancer therapy
- liver failure
- stem cells
- intensive care unit
- cell therapy
- insulin resistance
- adipose tissue
- bone marrow
- deep learning
- extracorporeal membrane oxygenation
- study protocol
- climate change
- artificial intelligence
- mechanical ventilation
- smoking cessation