Abstract 658: CBS9106 is a novel low toxic reversible oral CRM1 inhibitor with CRM1 degrading activity

Abstract

Abstract CRM1 plays an important role in the nuclear export of cargo proteins bearing Nuclear Exporting Signal sequences. Leptomycin B (LMB), a well-known irreversible inhibitor of CRM1, possesses strong anti-tumor properties, however, its toxicity prevents it from being clinically useful. In this study, we show that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export and induces G1-arrest and apoptosis in time- and dose-dependent manner in a broad-spectrum of cancer cells including multiple myeloma cells. IC50s of growth inhibition by CBS9106 (48h) are in the range from 46.7 to 366 nM in multiple myeloma cell lines (MM.1R, MM.1S, ARH-77 and RPMI-8226). In contrast with LMB, CBS9106 acts reversibly and reduces CRM1 protein without affecting the mRNA expression level. CBS9106-dependent reduction of CRM1 is abolished by MG132, a proteasome inhibitor. Pretreatment of cells with LMB suppresses CBS9106-induced CRM1 degradation. Moreover, CBS9106-biotin captured CRM1 in a pull down analysis and the amount of CRM1 captured by CBS9106-biotin was reduced by LMB treatment and vice versa. These results suggest that CBS9106 acts on the domain of CRM1 that includes LMB's covalent binding site at Cys-528, leading to proteasome-dependent CRM1 degradation. Oral administration of CBS9106 significantly suppressed tumor growth and prolonged survival duration in xenograft model mice. It caused prolonged reduction of CRM1 protein in tumor xenografts without showing significant body weight loss. Taken together, the results indicate that CBS9106 is a novel CRM1 inhibitor and a promising clinical candidate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2011-658