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KPT-276, analog of KPT-185, is a selective inhibitor of nuclear export (SINE) and CRM1 [1].

Chromosomemaintenance protein 1 (CRM1) is a nuclear export receptor involved in the active transport of transcription factors, cell-cycle regulators, tumor suppressors and RNA molecules. In cancer, CRM1 is overexpression and overactive transport [1].

KPT-276 is an orally bioavailable and selective CRM1 inhibitor that irreversibly binds to CRM1 and blocks CRM1-mediated nuclear export [1]. In human multiple myeloma (MM) cell lines (HMCLs), KPT-276 irreversibly and specifically inhibited the nuclear export of XPO1, which encoded CRM1 and significantly reduced the viability of HMCLs. In bone marrow cells isolated from MM patients, KPT-276 induced apoptosis. Also, KPT-276 downregulated the expression of c-MYC, CDC25A and BRD4, which caused G1/S phase arrest [2].

In a xenograft human acute myeloid leukemia (AML) murine model, KPT-276 significantly increased the survival of mice and reduced the amount of white blood cells. Also, KPT-276 significantly reduced spleen weight and FLT3 protein expression [1]. In a xenograft MM mouse model, KPT-276 inhibited tumor growth [2].

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