Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 15, Pages 4135-4150Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.05.056
Keywords
Fragment based hit discovery; FAXS-NMR screening; Structure-based design; Hsp90 inhibitors; Anti-cancer agents
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In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization. (C) 2014 Elsevier Ltd. All rights reserved.
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