SL-801, a Novel, Reversible Inhibitor of Exportin-1 (XPO1) / Chromosome Region Maintenance-1 (CRM1) with Broad and Potent Anti-Cancer Activity

XPO1/CRM1, the principal nuclear export protein in eukaryotic cells, is required for the nuclear-cytoplasmic transport of both proteins and RNAs. Overexpression of XPO1 is reported in many cancers, causing dysregulated protein localization, aberrant cell proliferation, and resistance to apoptosis, and is associated with aggressive characteristics and poor patient outcome. Recent work has revealed XPO1 to be a clinically relevant target, and nuclear export inhibitors have emerged as a new class of anti-cancer agents with clinical activity in multiple hematologic and solid malignancies. SL-801 is a novel small molecule that binds covalently to Cys528 of XPO1, blocking the ability of XPO1 to interact with substrate cargos (e.g., p53, FOXO, p21, p27, and others). In contrast to the prototypical XPO1 inhibitor leptomycin B, which binds irreversibly to XPO1 and caused significant toxicities in Phase 1 trials, SL-801 binding to XPO1 is reversible, a characteristic that may be exploited to maximize its therapeutic index. Exposure to SL-801 results in potent inhibition of XPO1-dependent nuclear export, cell cycle arrest, and induction of apoptosis in a time- and dose-dependent manner. Here, the anti-tumor activity of SL-801 was investigated against a panel of 240 cell lines representing a broad range of solid and hematologic malignancies and confirmed in several SCID xenograft models.