design, synthesis and characterization of a highly effective inhibitor for analog-sensitive (as) kinases设计、合成和表征的高效抑制剂analog-sensitive激酶().pdfVIP

Design, Synthesis and Characterization of a Highly Effective Inhibitor for Analog-Sensitive (as) Kinases 1 2 2 3 4 4 Michael Klein , Montse Morillas , Alexandre Vendrell , Lars Brive , Marinella Gebbia , Iain M. Wallace , 4 5 2 1 Guri Giaever , Corey Nislow , Francesc Posas , Morten Grøtli * ¨ ` 1 Medicinal Chemistry, Department of Chemistry, University of Gothenburg, Goteborg, Sweden, 2 Cell Signalling Unit, Department de Ciencies Experimentals i de la Salut, ` Universitat Pompeu Fabra (UPF), Parc de Recerca Biomedica de Barcelona (PRBB), Barcelona, Spain, 3 Department of Cell and Molecular Biology, University of Gothenburg, ¨ Goteborg, Sweden, 4 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada, 5 Department of Molecular Genetics, University of Toronto, Toronto, Canada Abstract Highly selective, cell-permeable and fast-acting inhibitors of individual kinases are sought-after as tools for studying the cellular function of kinases in real time. A combination of small molecule synthesis and protein mutagenesis, identified a highly potent inhibitor (1-Isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) of a rationally engineered Hog1 serine/threonine kinase (Hog1T100G). This inhibitor has been successfully used to study various aspects of Hog1 signaling, including a transient cell cycle arrest and gene expression changes mediated by Hog1 in re