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

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.