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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Cytokines / antagonists & inhibitors*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Structure
  • Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors*
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Phenotype
  • Picolines / chemistry
  • Picolines / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzamides
  • Cytokines
  • Enzyme Inhibitors
  • Picolines
  • STF-118804
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human
  • nicotinamide phosphoribosyltransferase, mouse