CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity

• Published in: Blood 2011-10, Vol.118 (14), p.3922-3931
• Main Authors: Sakakibara, Keiichi, Saito, Naoya, Sato, Takuji, Suzuki, Atsushi, Hasegawa, Yoko, Friedman, Jonathan M., Kufe, Donald W., VonHoff, Daniel D., Iwami, Tadahiko, Kawabe, Takumi
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Aminopyridines - pharmacology; Aminopyridines - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Exportin 1 Protein; Gene Expression Regulation, Neoplastic - drug effects; Hematologic and hematopoietic diseases; Humans; Karyopherins - antagonists & inhibitors; Karyopherins - genetics; Karyopherins - metabolism; Male; Medical sciences; Mice; Mice, SCID; Multiple Myeloma - drug therapy; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Proteasome Endopeptidase Complex - metabolism; Pyrrolidinones - pharmacology; Pyrrolidinones - therapeutic use; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Ubiquitin - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-01-333138

CRM1 plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Leptomycin B (LMB), a well-known CRM1 inhibitor, possesses strong antitumor properties. However, its toxicity prevents it from being clinically useful. In this study, we demonstrate that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export, causing arrest of the cell cycle and inducing apoptosis in a time- and dose-dependent manner for a broad spectrum of cancer cells, including multiple myeloma cells. CBS9106 reduces CRM1 protein levels significantly without affecting CRM1 mRNA expression. This effect could be reversed by adding bortezomib or LMB. Moreover, CBS9106-biotin allows capture of CRM1 protein by streptavidin beads in a competitive manner with LMB and vice versa. Mass spectrometric analysis shows that CBS9106 reacts with a synthetic CRM1 peptide that contains Cys528 but not with a Cys528 mutant peptide. Oral administration of CBS9106 significantly suppresses tumor growth and prolongs survival in mice bearing tumor xenograft without a significant loss in body weight. A reduced level of CRM1 protein is also observed in tumor xenografts isolated from mice treated with CBS9106. Taken together, these results indicate that CBS9106 is a novel reversible CRM1 inhibitor and a promising clinical candidate.