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

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

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-2778. doi: 10.1016/j.bmcl.2016.04.073.
Zacharia Cheruvallath 1,  Mingnam Tang 1,  Christopher McBride 1,  Mallareddy Komandla 1,  Joanne Miura 1,  Thu Ton-Nu 1,  Phil Erikson 1,  Jun Feng 1,  Pamela Farrell 2,  J David Lawson 3,  Darin Vanderpool 2,  Yiqin Wu 2,  Douglas R Dougan 4,  Artur Plonowski 2,  Corine Holub 2,  Chris Larson 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Takeda California, United States.
  • 2 Biological Sciences, Takeda California, United States.
  • 3 Computational Sciences, Takeda California, United States.
  • 4 Structural Biology, Takeda California, United States.
PMID: 27155900 DOI: 10.1016/j.bmcl.2016.04.073
Abstract

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 <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Keywords

FBDD; Fragment-based drug discovery; Indazole; MetAP2; Metalloprotease; Methionine aminopeptidase 2.

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