Discovery Of Potent, Reversible Metap2 Inhibitors Via Fragment Based Drug Discovery And Structure Based Drug Design-Part 1

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.