Abstract
NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor.
Keywords:
FBDD; FBLD; Fragment-based; NAMPT; NMR.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acrylamides / chemical synthesis
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Acrylamides / chemistry
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Acrylamides / pharmacology*
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Cytokines / antagonists & inhibitors*
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Cytokines / genetics
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Fluorescence Resonance Energy Transfer
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
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Nicotinamide Phosphoribosyltransferase / genetics
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Nicotinamide Phosphoribosyltransferase / metabolism
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology*
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Structure-Activity Relationship
Substances
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Acrylamides
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Cytokines
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Enzyme Inhibitors
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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Piperidines
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human