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Chem Biol. 2013 Nov 21;20(11):1352-63. doi: 10.1016/j.chembiol.2013.09.014. Epub 2013 Oct 31.

Next-generation NAMPT inhibitors identified by sequential high-throughput phenotypic chemical and functional genomic screens.

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1
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

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PMID:
24183972
PMCID:
PMC3881547
DOI:
10.1016/j.chembiol.2013.09.014
[Indexed for MEDLINE]
Free PMC Article

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