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 published the artcile< Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase>, Application In Synthesis of 112-63-0, the main research area is aurora kinase inhibitor GSK1070916 structure activity antitumor antiproliferative.
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with Ki* values of 0.38 ± 0.29 and 1.5 ± 0.4 nM, resp., and is >250-fold selective over Aurora A. Biochem. characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clin. compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC50 = 7 nM). I.p. administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clin. trials.
Journal of Medicinal Chemistry published new progress about Antiproliferative agents. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Application In Synthesis of 112-63-0.
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