KPT-185

KPT-185 is a potent, small molecule Selective Inhibitor of Nuclear Export (SINE) that specifically targets Exportin-1 (CRM1/XPO1). Developed by Karyopharm Therapeutics, it functions by covalently binding to the cysteine 528 (Cys528) residue in the cargo-binding pocket of CRM1, thereby blocking the nuclear-to-cytoplasmic export of various tumor suppressor proteins (TSPs) such as p53, p21, and FOXO. This inhibition leads to the nuclear accumulation and reactivation of these TSPs, which triggers apoptosis in malignant cells. While KPT-185 demonstrated significant anti-tumor activity in preclinical models of melanoma, chronic lymphocytic leukemia, and non-small cell lung cancer, it is primarily utilized as a chemical probe and tool compound in research due to its limited metabolic stability in vivo. More stable analogs, such as selinexor (KPT-330), have proceeded into clinical development and regulatory approval.