title: Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase.
abstract: 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.
authors.affiliation: Genentech, Inc., Department of Structural Biology, 1 DNA Way, South San Francisco, California 94080 (USA).
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Ho
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Liu
authors.forename: Xukun
authors.initials: X
authors.lastname: Chen
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; C000591022:GNE-617; D006574:Heterocyclic Compounds, 2-Ring; D013450:Sulfones; D010754:Phosphoribosyl Pyrophosphate; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: antitumor agents; inhibitor adducts; metabolism; product inhibition; protein structures