KPT-276

KPT-276, analog of KPT-185, is an orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of CRM1.IC50 value:Target: CRM1in vitro: A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway [1]. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome [3].in vivo: One week after leukemic cell inoculation, the mice were given KPT-276 at 150 mg/kg via oral gavage, 3 times a week, or vehicle control. KPT-276 has the identical CRM1 binding warhead and specificity as KPT-185, similar biologic activity in vitro, but superior oral bioavailability and pharmacokinetics, which allow it to be used in vivo. Mice were monitored for survival. Some mice were killed at day 21 to assess the effects of KPT-276 on leukemia burden by measuring spleen weight and white blood cell count [2]. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity [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]. Schmidt J, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013 Dec;27(12):2357-65.

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