Small Molecule Inhibitors of CRM1

The transport through the nuclear pore complex is used by cancer cells to evade tumorsuppressive

mechanisms. Several tumor-suppressors have been shown to be excluded

from the cell nucleus in cancer cells by the nuclear export receptor CRM1 and abnormal

expression of CRM1 is oncogenic. Inhibition of CRM1 has long been postulated as

potential approach for the treatment of cancer and to overcome therapy resistance.

Furthermore, the nuclear export of viral components mediated by the CRM1 is crucial in

various stages of the viral lifecycle and assembly of many viruses from diverse families,

including coronavirus. However, the first nuclear export inhibitors failed or never entered

into clinical trials. More recently CRM1 reemerged as a cancer target and a successful

proof of concept was achieved with the clinical approval of Selinexor. The chemical

complexity of natural products is a promising perspective for the discovery of new nuclear

export inhibitors with a favorable toxicity profile. Several screening campaigns have been

performed and several natural product-based nuclear export inhibitors have been

identified. With this review we give an overview over the role of CRM1-mediated

nuclear export in cancer and the effort made to identify and develop nuclear export

inhibitors in particular from natural sources.