Discovery of Aminoratjadone Derivatives as Potent Noncovalent CRM1 Inhibitors

Cancer cells frequently utilize elevated nuclear export
to escape
tumor suppression and gain proliferative advantage. Chromosome Region
Maintenance 1 (CRM1/XPO1) mediates macromolecule nuclear export and
plays an important role in tumorigenesis and progression. The clinical
approval of its covalent inhibitor KPT-330 (Selinexor) validates the
feasibility of targeting CRM1 to treat cancers. Here, we synthesized
four aminoratjadone derivatives and found that two of them, KL1 and KL2, are noncovalent CRM1 inhibitors.
The two compounds underwent spontaneous hydrolysis in aqueous buffers,
and the resulting products were more active against CRM1. High-resolution
crystal structures revealed the CRM1-binding mode of these compounds
and explained the observed structure–activity relationships.
In cells, KL1 and KL2 localized CRM1 in
the nuclear periphery and led to depletion of nuclear CRM1, thereby
inhibiting the nuclear export and growth of colorectal cancer cells
at submicromolar concentrations. This work lays the foundation for
further development of aminoratjadone-based noncovalent CRM1 inhibitors.