Journal
CHEMBIOCHEM
Volume 15, Issue 8, Pages 1121-1130Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201402023
Keywords
antitumor agents; inhibitor adducts; metabolism; product inhibition; protein structures
Funding
- Department of Energy's (DOE) Office of Science
- SSRL Structural Molecular Biology Program - DOE's Office of Biological and Environmental Research
- National Institutes of Health (NIH)
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Prolonged inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a strategy for targeting cancer metabolism. Many NAMPT inhibitors undergo NAMPT-catalyzed phosphoribosylation (pRib), a property often correlated with their cellular potency. To understand this phenomenon and facilitate drug design, we analyzed a potent cellularly active NAMPT inhibitor (GNE-617). A crystal structure of pRib-GNE-617 in complex with NAMPT protein revealed a relaxed binding mode. Consistently, the adduct formation resulted in tight binding and strong product inhibition. In contrast, a biochemically equipotent isomer of GNE-617 (GNE-643) also formed pRib adducts but displayed significantly weaker cytotoxicity. Structural analysis revealed an altered ligand conformation of GNE-643, thus suggesting weak association of the adducts with NAMPT. Our data support a model for cellularly active NAMPT inhibitors that undergo NAMPT-catalyzed phosphoribosylation to produce pRib adducts that retain efficient binding to the enzyme.
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