KOS-2464

KOS-2464 is a small molecule inhibitor of Chromosomal Region Maintenance 1 (CRM1), also known as Exportin-1 (XPO1). Developed by Kosan Biosciences (later acquired by Bristol Myers Squibb), it is a semi-synthetic analog of Leptomycin B (LMB) designed to offer improved potency and reduced toxicity compared to its parent compound. KOS-2464 functions by covalently binding to the Cys528 residue of CRM1, thereby blocking the nuclear export of various cargo proteins, including tumor suppressors like p53 and proteins involved in DNA repair like topoisomerase IIα. In preclinical models of multiple myeloma and acute myeloid leukemia (AML), KOS-2464 demonstrated potent anti-proliferative activity with low nanomolar IC50 values and showed synergistic effects when combined with conventional chemotherapeutics such as doxorubicin and daunomycin.