Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

Affiliation:	1. Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA;2. Cureveda, LLC, 1450 South Rolling Road, Halethorpe, MD 21227, USA;3. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA;4. Department of Chemistry, Temple University, Philadelphia, PA 19122, USA;1. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;2. Boehringer Ingelheim Pharma GmbH&Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riß, Germany;3. Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany;1. Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. New Modality Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;3. New Drug Regulatory Affairs Department, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;4. Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;5. Frontier Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;6. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;7. Biologics Pharmacology Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;8. Daiichi Sankyo India Pharma Pvt. Ltd, Village Sarhaul, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122015, Haryana, India;1. Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada;2. Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, USA;1. Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 51, 11158 Belgrade, Serbia;2. Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States;3. Institute for Medical Research, University of Belgrade, Dr. Subotića 4, 11129 Belgrade, Serbia;1. Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;2. Department of Molecular Structure and Characterization, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;3. Department of Molecular Structure and Characterization, Amgen Inc., 1120 Veterans Boulevard, So San Francisco, CA 94080-1985, USA;4. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;5. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA

Abstract:	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.

Keywords:	Fragment based hit discovery FAXS-NMR screening Structure-based design Hsp90 inhibitors Anti-cancer agents
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