5JFR

Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

Summary for 5JFR

• Entry DOI: 10.2210/pdb5jfr/pdb
• Related: 5JHU 5JI6
• Descriptor: Methionine aminopeptidase 2, MANGANESE (II) ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: hydrolase, peptidase, metal ion binding, proteolysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P50579
• Total number of polymer chains: 1
• Total formula weight: 41912.35

Authors

Dougan, D.R.,Lawson, J.D. (deposition date: 2016-04-19, release date: 2016-05-25, Last modification date: 2024-11-13)

Primary citation

McBride, C.,Cheruvallath, Z.,Komandla, M.,Tang, M.,Farrell, P.,Lawson, J.D.,Vanderpool, D.,Wu, Y.,Dougan, D.R.,Plonowski, A.,Holub, C.,Larson, C.
Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.
Bioorg.Med.Chem.Lett., 26:2779-2783, 2016

PubMed Abstract: Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

PubMed: 27136719
DOI: 10.1016/j.bmcl.2016.04.072

Experimental method

X-RAY DIFFRACTION (1.6 Å)