The novel kinesin spindle protein (KSP) inhibitor SB-743921 exhibits marked activity in in vivo and in vitro models of aggressive large B-cell lymphoma
- Leuk Lymphoma. 2015;56(10):2945-52. doi: 10.3109/10428194.2015.1020058.
- 1. a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
- 2. b Department of Pathology , Columbia University Medical Center , NY , USA.
- 3. c Cytokinetics , South San Francisco , CA , USA.
The Kinesin spindle protein (KSP) is a mitotic protein essential for cell cycle control and motility. SB-743921 (hereafter SB-921) is an inhibitor that selectively targets the ATP-binding domain of the KSP. The preclinical activity of SB-921 was evaluated in models of Diffuse Large B-cell Lymphoma (DLBCL). The cytotoxicity of SB-921 was evaluated in a series of germinal center (GC-DLBCL) and post-germinal center (ABC-DLBCL) DLBCL cell lines and a murine lymphoma xenograft model. GC-DLBCL lines generally demonstrated greater sensitivity to SB-921. IC50 values ranged between 1 nM and 900 nM for GC-DLBCL compared to 1 nM to 10 μM for ABC lines. SB-921 demonstrated marked activity in a xenograft model of Ly-1 (GC-DLBCL). While SB-921 was relatively more active in GC derived cell lines, ABC-derived lines still underwent Apoptosis at higher concentrations. These results demonstrate that SB-921 inhibits proliferation and induces Apoptosis in both GC-DLBCL and ABC-DLBCL.