KPT 251

KPT-251 is an orally active chromosome region maintenance 1 protein (CRM1) inhibitor. KPT-251 induces cancer cell apoptosis and shows antileukemic activity[1][2].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Membrane Transporter/Ion Channel >> CRM1

KPT-251 binds in the NES-binding groove, which is located on the central, convex side of the CRM1 ring[1]. KPT-251 (72 h) suppresses melanoma cell proliferation[2]. KPT-251 (1 μM, 0-48 h) modulates levels of p53, pRb, survivin, and ERK phosphorylation[2]. KPT-251 (0.1 and 1 μM, 0-72 h) induces cell-cycle arrest and apoptosis[2]. Western Blot Analysis[2] Cell Line: Melanoma BRAF WT (Mewo) and mutant cells (A375) Concentration: 1 μM Incubation Time: 4, 8, 24 and 48 h Result: Prevented cytoplasmic p53 degradation, decreased survivin levels, increased ERK phosphorylation in both BRAF WT and mutant and reduced pRb and p-pRb levels. Cell Cycle Analysis[2] Cell Line: Mewo and A375 cells Concentration: 1 μM Incubation Time: 24, 48 and 72 h Result: Reduced S-phase, both G1 and/or G2 cell-cycle arrest can be observed. Apoptosis Analysis[2] Cell Line: Mel-Juso, SK-MEL-28, SK-MEL-5 and A375 cells Concentration: 0.1 and 1 μM Incubation Time: 24, 48 and 72 h Result: Increased caspase-3 and -7 activity in the tested melanoma cell lines in a dose- and time-related manner.

KPT-251 (75 mg/kg/day; i.g.; three times per week for 5 weeks) effectively suppresses the growth of MV4-11 cells engrafted into NSG mice and provides a significant survival benefit[1].KPT-251 (50 mg/kg; p.o.; every other day for 21 days) suppresses tumor growth in mice melanoma xenograft models[2]. Animal Model: 7-weekold female NOD-SCID-IL2Rcγnull (NSG) mice, introduced 2 × 106 luciferase-expressing MV4-11 cells via tail-vein injections[1] Dosage: 75 mg/kg/day Administration: Gavage, three times per week for 5 weeks Result: Exhibited significantly increased survival with leukemia progression occurring only after cessation of treatment, prevented infiltration of leukemia cells into mouse bone marrow and spleen, and spared normal hematopoietic cells. Animal Model: Athymic nude mice Nu/Nu, melanoma xenograft models[2] Dosage: 50 mg/kg Administration: Oral, every other day for 21 days Result: Suppressed tumor growth, increased cleaved caspase-3 and decreased Ki67.

[1]. Etchin J, et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia. 2013 Jan;27(1):66-74.

[2]. Salas Fragomeni RA, et al. CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF-mutant melanoma. Mol Cancer Ther. 2013 Jul;12(7):1171-9.