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Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling

Academic Article
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Overview

related to degree

  • Evans, Michael, Ph.D. in Chemistry, Scripps Research 2001 - 2007

authors

  • Evans, Michael
  • Saghatelian, Alan
  • Sorensen, Erik J.
  • Cravatt, Benjamin

publication date

  • 2005

journal

  • Nature Biotechnology  Journal

abstract

  • Chemical genomics aims to discover small molecules that affect biological processes through the perturbation of protein function. However, determining the protein targets of bioactive compounds remains a formidable challenge. We address this problem here through the creation of a natural product-inspired small-molecule library bearing protein-reactive elements. Cell-based screening identified a compound, MJE3, that inhibits breast cancer cell proliferation. In situ proteome reactivity profiling revealed that MJE3, but not other library members, covalently labeled the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), resulting in enzyme inhibition. Interestingly, MJE3 labeling and inhibition of PGAM1 were observed exclusively in intact cells. These results support the hypothesis that cancer cells depend on glycolysis for viability and promote PGAM1 as a potential therapeutic target. More generally, the incorporation of protein-reactive compounds into chemical genomics screens offers a means to discover targets of bioactive small molecules in living systems, thereby enabling downstream mechanistic investigations.

subject areas

  • Antineoplastic Agents
  • Biological Assay
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Delivery Systems
  • Drug Design
  • Humans
  • Phosphoglycerate Mutase
  • Protein Interaction Mapping
  • Proteome
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Identity

International Standard Serial Number (ISSN)

  • 1087-0156

Digital Object Identifier (DOI)

  • 10.1038/nbt1149

PubMed ID

  • 16200062
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Additional Document Info

start page

  • 1303

end page

  • 1307

volume

  • 23

issue

  • 10

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