Discovery of novel XPO1 PROTAC degraders for the treatment of acute myeloid leukemia

Abstract

Targeting XPO1 inhibition has emerged as a promising therapeutic strategy in cancer treatment. Despite the numerous XPO1 inhibitors reported to date, no XPO1 degraders have been disclosed. In this study, we reported the design, synthesis and biological characterization of small-molecule XPO1 degraders based upon the proteolysis targeting chimera (PROTAC), marking the first public disclosure of XPO1 degraders. The potent PROTAC compound 2c was identified, demonstrating effective degradation of XPO1 protein in MV4-11 acute myeloid leukemia (AML) cells, with a DC50 of 23.67 nM. Treatment with 2c resulted in significant antiproliferative effects, with IC50 values of 0.142 ± 0.029 μM in MV4-11 cells and 0.186 ± 0.024 μM in MOLM-13 cells. Additionally, 2c induced apoptosis, inhibited NF-κB activity, and caused G1 phase cell cycle arrest. The study highlights the therapeutic potential of targeting XPO1 degradation in AML treatment and emphasizes the advantages of PROTAC technology in developing novel anticancer strategies. These findings provide a foundation for further exploration of XPO1 degraders in cancer therapy, offering new hope for effective treatment options in hematological malignancies.

Keywords: AML; MV4-11 cells; PROTAC; Protein degradation; XPO1.