A novel class of reversible Exportin-1 inhibitors for cancer therapy

Selective partitioning of macromolecules between the nucleus and the cytoplasm, also called the nuclear-cytoplasmic transport, offers an additional way of regulating protein function in eukaryotic cells. However, alterations in this process causing mislocalization of proteins such as tumor suppressors or oncoproteins may result in uncontrolled cell growth and carcinogenesis. Therefore, restoring proper protein localisation by modulating nuclear-cytoplasmic transport is a promising therapeutic anticancer strategy. Recently, the first clinical validation for targeting nuclear transport as a genuine target for cancer therapy came from selinexor, the first small molecule exportin-1 inhibitor reaching patients. Selinexor was recently approved by the FDA for the treatment of patients with triple-class refractory multiple myeloma. It is a covalent and irreversible inhibitor of exportin-1 function. We now have discovered a novel drug-like compound class with a reversible mechanism of action. The aim of this project is to evaluate the in vivo efficacy and tolerability of this novel compound class in small animal models.

Keywords:Cancer, nuclear-cytoplasmic transport, small-molecule inhibitors

Disciplines:Cancer therapy