KPT-276

KPT-276 is a small molecule, selective inhibitor of nuclear export (SINE) that was developed by Karyopharm Therapeutics. It functions by specifically binding to and inhibiting Exportin 1 (XPO1/CRM1), the major nuclear export protein responsible for the transport of tumor suppressor proteins (TSPs), such as p53, p21, and BRCA1, out of the nucleus. By blocking this export pathway, KPT-276 forces the nuclear accumulation and functional reactivation of these TSPs, which triggers cell cycle arrest and apoptosis in various cancer cells, including melanoma. Preclinical studies demonstrated that KPT-276 possesses high oral bioavailability and significant anti-tumor activity in xenograft models. Although KPT-276 showed promise, Karyopharm ultimately prioritized the development of its related compound, selinexor (KPT-330), for clinical use.