1. Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase
- Author
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Octerloney B. McDonald, Carla A. Donatelli, William F. Huffman, Toshihiro Hamajima, Christine Thompson, Kelly E. Fisher, Martha A. Sarpong, Jamin C Wang, David Sutton, Dashyant Dhanak, Peter J. Tummino, Jun Tang, Ken A. Newlander, Zhihong V Lai, Hong Xiang, Kosuke Sasaki, Domingos J. Silva, Mary Ann Hardwicke, Jerry L. Adams, Cynthia A. Parrish, Schmidt Stanley J, Denis R. Patrick, Hiroko Nakamura, Jingsong Yang, Catherine A. Oleykowski, Robert A. Copeland, Amita M. Chaudhari, Ramona Plant, David H. Drewry, Kristin K Koretke-Brown, Nicholas D. Adams, and Joelle Lorraine Burgess
- Subjects
Indoles ,Transplantation, Heterologous ,Aurora inhibitor ,Aurora B kinase ,Protein Serine-Threonine Kinases ,Histones ,Mice ,Structure-Activity Relationship ,Histone H3 ,Aurora kinase ,Aurora Kinases ,Cell Line, Tumor ,Drug Discovery ,Animals ,Aurora Kinase B ,Humans ,Phosphorylation ,Aurora Kinase A ,Aza Compounds ,Kinase ,Chemistry ,Stereoisomerism ,Transplantation ,Biochemistry ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Neoplasm Transplantation - Abstract
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 K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal 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 clinical trials.
- Published
- 2010