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The Discovery of PLK4 Inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimi...

Authors:   Radoslaw Laufer; Bryan Forrest; Sze-Wan Li; Yong Liu; Peter Sampson; Louise Edwards; Yunhui Lang; Donald E. Awrey; Guodong Mao; Olga Plotnikova; Genie Leung; Richard Hodgson; Irina Beletskaya; Jacqueline M. Mason; Xunyi Luo; Xin Wei; Yi Yao; Miklos Feher; Fuqiang Ban; Reza Kiarash; Erin Green; Tak W. Mak; Guohua Pan; Henry W. Pauls
Journal:   Journal of Medicinal Chemistry
Year:   2013
DOI:   10.1021/jm400380m
Publication date:   26-Jul-2013
Facts, background information, dossiers
  • kinases
  • cell cycle
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