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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Cheruvallath, Zacharia¹  Tang, Mingnam¹  McBride, Christopher¹  Komandla, Mallareddy¹  Miura, Joanne¹  Ton-Nu, Thu¹  Erikson, Phil¹  Feng, Jun¹  Farrell, Pamela²  Lawson, J. David³  Vanderpool, Darin²  Wu, Yiqin²  Dougan, Douglas R.⁴  Plonowski, Artur²  Holub, Corine²  Larson, Chris² 

[1] Takeda Calif, Med Chem, San Diego, CA USA

[2] Takeda Calif, Biol Sci, San Diego, CA USA

[3] Takeda Calif, Computat Sci, San Diego, CA USA

[4] Takeda Calif, Struct Biol, San Diego, CA USA

关键词: FBDD;    Fragment-based drug discovery;    MetAP2;    Methionine aminopeptidase 2;    Metalloprotease;    Indazole;   

DOI  :  10.1016/j.bmcl.2016.04.073

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free