title: Next-generation NAMPT inhibitors identified by sequential high-throughput phenotypic chemical and functional genomic screens.
abstract: Phenotypic high-throughput chemical screens allow for discovery of small molecules that modulate complex phenotypes and provide lead compounds for novel therapies; however, identification of the mechanistically relevant targets remains a major experimental challenge. We report the application of sequential unbiased high-throughput chemical and ultracomplex small hairpin RNA (shRNA) screens to identify a distinctive class of inhibitors that target nicotinamide phosphoribosyl transferase (NAMPT), a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide, a crucial cofactor in many biochemical processes. The lead compound STF-118804 is a highly specific NAMPT inhibitor, improves survival in an orthotopic xenotransplant model of high-risk acute lymphoblastic leukemia, and targets leukemia stem cells. Tandem high-throughput screening using chemical and ultracomplex shRNA libraries, therefore, provides a rapid chemical genetics approach for seamless progression from small-molecule lead identification to target discovery and validation.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Matheny
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wei
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Donnelly
authors.forename: Martin
authors.initials: M
authors.lastname: Kampmann
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Obdulio
authors.initials: O
authors.lastname: Piloto
authors.forename: David E
authors.initials: DE
authors.lastname: Solow-Cordero
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bouley
authors.forename: Rachel
authors.initials: R
authors.lastname: Rau
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: Michael T
authors.initials: MT
authors.lastname: McManus
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Weissman
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015394:Molecular Structure; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010847:Picolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D004791:Enzyme Inhibitors; D010847:Picolines; C000593977:STF-118804; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C495867:nicotinamide phosphoribosyltransferase, mouse