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Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-2778. doi: 10.1016/j.bmcl.2016.04.073. Epub 2016 Apr 25.

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

Author information

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.

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

PMID:
27155900
DOI:
10.1016/j.bmcl.2016.04.073
[Indexed for MEDLINE]

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