title: 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.
abstract: 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.
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
authors: Danielle
authors: D
authors: Bongero
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
authors: Luca
authors: L
authors: Paoluzzi
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
authors: Enrica
authors: E
authors: Marchi
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
authors: Kelly M
authors: KM
authors: Zullo
authors: b Department of Pathology , Columbia University Medical Center , NY , USA.
authors: Roberto
authors: R
authors: Neisa
authors: b Department of Pathology , Columbia University Medical Center , NY , USA.
authors: Yinghui
authors: Y
authors: Mao
authors: c Cytokinetics , South San Francisco , CA , USA.
authors: Rafael
authors: R
authors: Escandon
authors: c Cytokinetics , South San Francisco , CA , USA.
authors: Ken
authors: K
authors: Wood
authors: a Center for Lymphoid Malignancies, Department of Medicine , Columbia University Medical Center , NY , USA.
authors: Owen A
authors: OA
authors: O'Connor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D020128:Inhibitory Concentration 50; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008938:Mitosis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D002867:Chromones; C470243:KIF11 protein, human; C557279:SB 743921; D016547:Kinesins
keywords: Diffuse large B-cell lymphoma non-Hodgkin lymphoma; SB-743921; kinesin spindle protein