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IWASAKI Masayuki
Department Research Institutes and Facilities, Research Institutes and Facilities Position Assistant Professor |
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| Article types | Original article |
| Language | English |
| Peer review | Peer reviewed |
| Title | Next-generation NAMPT inhibitors identified by sequential high-throughput phenotypic chemical and functional genomic screens. |
| Journal | Formal name：Chemistry & biology Abbreviation：Chem Biol ISSN code：18791301/10745521 |
| Domestic / Foregin | Foregin |
| Volume, Issue, Page | 20(11),pp.1352-63 |
| Author and coauthor | Matheny Christina J, Wei Michael C, Bassik Michael C, Donnelly Alicia J, Kampmann Martin, Iwasaki Masayuki, Piloto Obdulio, Solow-Cordero David E, Bouley Donna M, Rau Rachel, Brown Patrick, McManus Michael T, Weissman Jonathan S, Cleary Michael L |
| Publication date | 2013/11 |
| Summary | 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. |
| DOI | 10.1016/j.chembiol.2013.09.014 |
| PMID | 24183972 |