KPT-185

KPT-185 is an orally bioavailable selective inhibitor of CRM1 amd displayes potent antiproliferative properties at submicromolar concentrations (IC50 values:100-500nM), induced apoptosis (average 5-fold increase), cell-cycle arrest, and myeloid differentiation in AML cell lines and patient blasts.IC50 value: 100-500 nM (AML cell lines) [1]Target: CRM1in vitro: Submicromolar concentrations of KPT-185 inhibited leukemia cell proliferation, with IC50 values ranging from 100nM to 500nM (MV4-11, Kasumi-1, OCI/AML3, MOLM-13, KG1a, and THP-1). KPT-185 at the predetermined IC50 value induced cell-cycle arrest at G1 with respect to vehicle-treated-control (DMSO) in MV4-11 (82.2% ± 3.69% vs 71.55% ± 0.21%, P < .01), OCI/AML3 (83.05% ± 6.84% vs 55.1% ± 2.26%, P < .01), and MOLM-13 (82.72% ± 1.14% vs 57.55 ± 3.46%, P < .01) cells at 24 hours. A significant accumulation of p53 in the nucleus of MV4-11 and OCI-AML3 was observed after treatment with KPT-185 [1]. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome [2]. in vivo: In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition [3].

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

Research Areas >> Cancer

[1]. Ranganathan P, et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. 2012 Aug 30;120(9):1765-73.

[2]. Zhang K, et al. Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma. Exp Hematol. 2013 Jan;41(1):67-78.e4.

[3]. 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.

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