IWASAKI Masayuki
   Department   Research Institutes and Facilities, Research Institutes and Facilities
   Position   Assistant Professor
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 / ForeginForegin
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