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Next-generation NAMPT Inhibitors Identified by Sequential High-Throughput Phenotypic Chemical and Functional Genomic Screens

Next-generation NAMPT Inhibitors Identified by Sequential High-Throughput Phenotypic Chemical and Functional Genomic Screens

Christina J Matheny, Michael C Wei, Michael C Bassik, Alicia J Donnelly, Martin Kampmann, Masayuki Iwasaki, Obdulio Piloto, David E Solow-Cordero, Donna M Bouley, Rachel Rau, Patrick Brown, Michael T McManus, etc.

Chem Biol. 2013 Nov 21;20(11):1352-63.

PMID: 24183972

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP894187612	STF-118804		894187-61-2	Price

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