discovery of potent, reversible metap2 inhibitors via fragment based drug discovery and structure based drug design—part 1：（发现的,可逆metap2抑制剂通过基于片段的药物发现和基于结构的药物设计）.pdfVIP

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discovery of potent, reversible metap2 inhibitors via fragment based drug discovery and structure based drug design—part 1：（发现的,可逆metap2抑制剂通过基于片段的药物发现和基于结构的药物设计）.pdf

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discovery of potent, reversible metap2 inhibitors via fragment based drug discovery and structure based drug design—part 1：（发现的,可逆metap2抑制剂通过基于片段的药物发现和基于结构的药物设计）

Bioorganic Medicinal Chemistry Letters 26 (2016) 2774–2778 Contents lists available at ScienceDirect Bioorganic Medicinal Chemistry Letters journal homepage: /locate/bmcl Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design—Part 1 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 a Medicinal Chemistry, Takeda California, United States b Biological Sciences, Takeda California, United States c Computational Sciences, Takeda California, United States d Structural Biology, Takeda California, United States a r t i c l e i n f o a b s t r a c t Article history: Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue Received 29 February 2016 from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhi- Revised 22 April 2016 bitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening Accepted 23 April 2016 methods and structural biology to quickly identify and elaborate an indazole fragment into a series of Available online 25 April 2016 reversible MetAP2 inhibitors with 10 nM potency, excellent selectivity, and favorable in vitro safety