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, Jonathan S. Weissman, Michael L. Cleary

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1352-1363
Number of pages12
JournalChemistry and Biology
Volume20
Issue number11
DOIs
StatePublished - Nov 21 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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