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GSK1070916

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]

Current developer:    GlaxoSmithKline

 1. Adams, Nicholas D.; Adams, Jerry L.; Burgess, Joelle L.; Chaudhari, Amita M.; Copeland, Robert A.; Donatelli, Carla A.; Drewry, David H.; Fisher, Kelly E.; Hamajima, Toshihiro; Hardwicke, Mary Ann; Huffman, William F.; Koretke-Brown, Kristin K.; Lai, Zhihong V.; McDonald, Octerloney B.; Nakamura, Hiroko; Newlander, Ken A.; Oleykowski, Catherine A.; Parrish, Cynthia A.; Patrick, Denis R.; Plant, Ramona; Sarpong, Martha A.; Sasaki, Kosuke; Schmidt, Stanley J.; Silva, Domingos J.; Sutton, David; Tang, Jun; Thompson, Christine S.; Tummino, Peter J.; Wang, Jamin C.; Xiang, Hong; Yang, Jingsong; Dhanak, Dashyant. Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase. Journal of Medicinal Chemistry (2010), 53(10), 3973-4001. 

2. Medina, Jesus R.; Grant, Seth W.; Axten, Jeffrey M.; Miller, William H.; Donatelli, Carla A.; Hardwicke, Mary Ann; Oleykowski, Catherine A.; Liao, Qiaoyin; Plant, Ramona; Xiang, Hong. Discovery of a new series of Aurora inhibitors through truncation of GSK1070916. Bioorganic & Medicinal Chemistry Letters (2010), 20(8), 2552-2555. 

3. Hardwicke, Mary Ann; Oleykowski, Catherine A.; Plant, Ramona; Wang, Jamin; Liao, Qiaoyin; Moss, Katherine; Newlander, Ken; Adams, Jerry L.; Dhanak, Dashyant; Yang, Jingsong; Lai, Zhihong; Sutton, David; Patrick, Denis. GSK1070916, a potent Aurora B/C kinase inhibitor with broad antitumor activity in tissue culture cells and human tumor xenograft models. Molecular Cancer Therapeutics (2009), 8(7), 1808-1817. 

4. Anderson, Kelly; Lai, Zhihong; McDonald, Octerloney B.; Stuart, J. Darren; Nartey, Eldridge N.; Hardwicke, Mary Ann; Newlander, Ken; Dhanak, Dashyant; Adams, Jerry; Patrick, Denis; Copeland, Robert A.; Tummino, Peter J.; Yang, Jingsong. Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1. Biochemical Journal (2009), 420(2), 259-265. 

5. Dhanak, Dashyant; Newlander, Kenneth Allen. Preparation of azaindoles as aurora kinase inhibitors for the treatment of cancer. U.S. Pat. Appl. Publ. (2007), 108 pp. CODEN: USXXCO US 2007149561 A1 20070628 CAN 147:118204 AN 2007:701111