title: GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models.
abstract: The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. Human tumor cells treated with GSK1070916 show dose-dependent inhibition of phosphorylation on serine 10 of Histone H3, a substrate specific for Aurora B kinase. Moreover, GSK1070916 inhibits the proliferation of tumor cells with EC(50) values of <10 nmol/L in over 100 cell lines spanning a broad range of tumor types. Although GSK1070916 has potent activity against proliferating cells, a dramatic shift in potency is observed in primary, nondividing, normal human vein endothelial cells, consistent with the proposed mechanism. We further determined that treated cells do not arrest in mitosis but instead fail to divide and become polyploid, ultimately leading to apoptosis. GSK1070916 shows dose-dependent inhibition of phosphorylation of an Aurora B-specific substrate in mice and consistent with its broad cellular activity, has antitumor effects in 10 human tumor xenograft models including breast, colon, lung, and two leukemia models. These results show that GSK1070916 is a potent Aurora B/C kinase inhibitor that has the potential for antitumor activity in a wide range of human cancers.
authors: Oncology Biology, GlaxoSmithKline, Collegeville, PA 19426, USA. Mary.Ann.Hardwicke-1@GSK.com
authors: Mary Ann
authors: MA
authors: Hardwicke
authors: Catherine A
authors: CA
authors: Oleykowski
authors: Ramona
authors: R
authors: Plant
authors: Jamin
authors: J
authors: Wang
authors: Qiaoyin
authors: Q
authors: Liao
authors: Katherine
authors: K
authors: Moss
authors: Ken
authors: K
authors: Newlander
authors: Jerry L
authors: JL
authors: Adams
authors: Dashyant
authors: D
authors: Dhanak
authors: Jingsong
authors: J
authors: Yang
authors: Zhihong
authors: Z
authors: Lai
authors: David
authors: D
authors: Sutton
authors: Denis
authors: D
authors: Patrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001372:Aza Compounds / Q000627:therapeutic use*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; C544308:GSK 1070916; D007211:Indoles; D047428:Protein Kinase Inhibitors; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases