Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 12, Pages 2774-2778Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.04.073
Keywords
FBDD; Fragment-based drug discovery; MetAP2; Methionine aminopeptidase 2; Metalloprotease; Indazole
Categories
Funding
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
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Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with < 10 nM potency, excellent selectivity, and favorable in vitro safety profiles. (C) 2016 Elsevier Ltd. All rights reserved.
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