Selective inhibitor of nuclear export

The prototypical nuclear export inhibitor is leptomycin B, a natural product and secondary metabolite of Streptomyces bacteria.

Although it is nonselective and too toxic for clinical use in humans, the discovery of its mechanism of action and antitumor properties prompted development of the SINE compounds.

[1] SINEs work by binding to CRM1, a karyopherin which performs nuclear transport of hundreds of proteins—including tumor suppressors, oncogenes, and proteins involved in governing cell growth—from the cell nucleus to the cytoplasm.

[1] By restoring nuclear transport of these proteins to normal, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell growth, ultimately triggering apoptosis.

[1] Nevertheless, because CRM1 is a pleiotropic gene, inhibiting it affects many different systems in the body, which causes a high rate of adverse reactions.

Schematic illustration of the Ran cycle of nuclear transport. SINE compounds inhibit this process at the nuclear export receptor (upper right).