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
  • 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.