GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models

Molecular Cancer Therapeutics - Tập 8 Số 7 - Trang 1808-1817 - 2009
Mary Ann Hardwicke1, Catherine A. Oleykowski1, Ramona Plant1, Jamin Wang1, Qiaoyin Liao1, Katherine G. Moss1, Kenneth A. Newlander1, Jerry L. Adams1, Dashyant Dhanak1, Jinsong Yang1, Zhihong Lai1, David Sutton1, Denis R. Patrick1
11Oncology Biology, 2Medicinal Chemistry, 3Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, Collegeville, Pennsylvania

Tóm tắt

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 EC50 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. [Mol Cancer Ther 2009;8(7):1808–17]

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Tài liệu tham khảo

Carmena, 2003, The cellular geography of aurora kinases, Nat Rev Mol Cell Biol, 4, 842, 10.1038/nrm1245

Nigg, 2001, Mitotic kinases as regulators of cell division and its checkpoints, Nat Rev Mol Cell Biol, 2, 21, 10.1038/35048096

Bischoff, 1999, The Aurora/IpI1p kinase family: regulators of chromosome segregation and cytokinesis, Trends Cell Biol, 9, 454, 10.1016/S0962-8924(99)01658-X

Kawasaki, 2001, Downregulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells, J Cell Biol, 152, 275, 10.1083/jcb.152.2.275

Kimura, 1997, Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase Aik related to Aurora of Drosophila and yeast Ipl1, J Biol Chem, 272, 13766, 10.1074/jbc.272.21.13766

Terada, 1998, AIM-1: a mammalian midbody-associated protein required for cytokinesis, EMBO J3, 17, 667, 10.1093/emboj/17.3.667

Farruggio, 1999, Cdc20 associates with the kinase aurora2/Aik, Proc Natl Acad Sci U S A, 96, 7306, 10.1073/pnas.96.13.7306

Nguyen, 2005, Mechanism of Aurora B degradation and its dependency on intact KEN and A-boxes: identification of an aneuploidy-promoting property, Mol Cell Biol, 25, 4977, 10.1128/MCB.25.12.4977-4992.2005

Taguchi, 2002, Degradation of human Aurora A protein kinase is mediated by hCdh1, FEBS Lett, 519, 59, 10.1016/S0014-5793(02)02711-4

Crane, 2004, Requirements for the destruction of human Aurora-A, J Cell Sci, 117, 5975, 10.1242/jcs.01418

Sasai, 2004, Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells, Cell Motil Cytoskeleton, 59, 249, 10.1002/cm.20039

Adams, 2001, Chromosomal passengers and the (aurora) ABCs of mitosis, Trends Cell Biol, 11, 49, 10.1016/S0962-8924(00)01880-8

Carvajal, 2006, Aurora kinases: new targets for cancer therapy, Clin Cancer Res, 12, 6869, 10.1158/1078-0432.CCR-06-1405

Kallio, 2002, Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis, Curr Biol, 12, 900, 10.1016/S0960-9822(02)00887-4

Tatsuka, 1998, Multinuclearity and increased ploidy caused by overexpression of the aurora B and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells, Cancer Res, 58, 4811

Chieffi, 2006, Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation, Prostate, 66, 326, 10.1002/pros.20345

Sorrentino, 2005, Aurora B over expression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation, J Clin Endocrinol Metab, 90, 928, 10.1210/jc.2004-1518

Vischioni, 2006, Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell ling carcinoma patients, Mol Cancer Ther, 5, 2905, 10.1158/1535-7163.MCT-06-0301

Zeng, 2007, Aurora B expression correlates with aggressive behavior in glioblastoma multiforme, J Clin Pathol, 60, 218, 10.1136/jcp.2006.036806

Matthews, 2006, Aurora A and B kinases as targets for cancer: Will they be selective for tumors?, Expert Rev Anticancer Ther, 6, 109, 10.1586/14737140.6.1.109

Keen, 2004, Aurora-kinase inhibitors as anticancer agents, Nat Rev Cancer, 4, 927, 10.1038/nrc1502

Mahadevan, 2007, Aurora kinase targeted therapeutics in oncology:past, present and future, Expert Opin Drug Discov, 2, 1011, 10.1517/17460441.2.7.1011

Ikezoe, 2008, Aurora kinase as an anti-cancer target, Cancer Lett, 262, 1, 10.1016/j.canlet.2008.01.005

Vindeløv, 1983, A Detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis, Cytometry, 3, 323, 10.1002/cyto.990030503

Ward, 2004, Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey, J Pharmacol Exp Ther, 310, 703, 10.1124/jpet.104.068288

Ditchfield, 2003, Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores, J Cell Biol, 161, 267, 10.1083/jcb.200208091

Peterson, 2003, S.pombe aurora kinase/survivin is required for chromosome condensation and the spindle checkpoint attachment response, Curr Biol, 13, 590, 10.1016/S0960-9822(03)00205-7

Yang, 2005, Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase, FEBS Lett, 579, 3385, 10.1016/j.febslet.2005.04.080

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Molecular Cancer Therapeutics

Tập 8 Số 7

1808-1817

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