Probing 2H-Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors |
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| Authors: | Jens Schoene Thais Gazzi Dr. Peter Lindemann Prof. Dr. Mathias Christmann Prof. Dr. Andrea Volkamer Dr. Marc Nazaré |
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| Affiliation: | 1. Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus BerlinBuch, Robert-Roessle-Str. 10, 13125 Berlin, Germany;2. Organische Chemie, Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse. 3, 14195 Berlin, Germany;3. In silico Toxicology and Structural Bioinformatics Group, Institute of Physiology, Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany |
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| Abstract: | The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so-far underrepresented aza-2H-indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC50 values in the range of 500 nm . In a comparative computational study, these data were analyzed and rationalized in light of docking studies. |
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| Keywords: | docking drug design focused library kinase inhibition nitrogen heterocycles scaffolds |
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