Evaluation of KPT-SINE (Selective Inhibitors of CRM1-Mediated Nuclear Export) in AML and T-ALL.

e13586 Background: CRM1 is the major nuclear exporter that mediates transport of a variety of molecules, including proteins involved in tumor suppressor and cellular proliferation pathways. The crystal structure of CRM1, in complex with its export cargo, Snurportin 1, has been recently resolved. The molecular understanding of the CRM1-cargo binding interface has led to the development of novel small molecule inhibitors of CRM1-cargo interaction, termed KPT-Selective Inhibitors of Nuclear Export (SINE). KPT-SINE are potent, drug-like CRM1 inhibitors that irreversibly inactivate the CRM1-directed protein export by covalent modification of the essential CRM1-cargo binding residue Cys528. The inhibition of the CRM1 nuclear export has been shown to lead to selective apoptosis in cancer cells when compared to normal cells. Here, we assess the efficacy of the KPT-SINE in human AML, T-ALL, and normal hematopoietic cells. Methods: The viability of a panel of human AML and T-ALL cell lines upon treatment by the KPT...