Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design—Part 1

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• 作者：Zacharia Cheruvallath^a ; ; Mingnam Tang^a ; Christopher McBride^a ; Mallareddy Komandla^a ; Joanne Miura^a ; Thu Ton-Nu^a ; Phil Erikson^a ; Jun Feng^a ; Pamela Farrell^b ; J. David Lawson^c ; Darin Vanderpool^b ; Yiqin Wu^b ; Douglas R. Dougan^d ; Artur Plonowski^b ; Corine Holub^b ; Chris Larson^b
• 关键词：FBDD ; Fragment-based drug discovery ; MetAP2 ; Methionine aminopeptidase 2 ; Metalloprotease ; Indazole
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：26
• 期：12
• 页码：2774-2778
• 全文大小：2257 K

文摘

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.