NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter

J Med Chem. 2004 Sep 23;47(20):4851-7. doi: 10.1021/jm0497803.


Reversal of aberrant gene expression that is induced by the proto-oncogene c-myc is likely to be effective for treating a variety of tumors that rely on this pathway for growth. One strategy to down-regulate the c-myc pathway is to target transcription factors that regulate its own expression. A host of proteins act in coordination to regulate c-myc expression and any one of them are theoretical targets for small-molecule therapy. Experimentally, it has been shown that the far upstream element (FUSE) binding protein (FBP) is essential for c-myc expression, and reductions in FBP levels both reduce c-myc expression and correlate with slower cell growth. FBP binds to ssDNA by capturing exposed DNA bases in a hydrophobic pocket. This suggests that a small molecule could be designed to occupy this pocket and inhibit FBP function. Using a variety of screening methodologies, we have identified ligands that bind to the DNA binding pockets of the KH domains of FBP. Gel shift analyses using full length FBP and a related transcription factor confirm that a small-molecule lead compound inhibits DNA binding in a specific manner. The benzoylanthranilic acid compounds described here represent leads in the design of FBP inhibitors that can serve as useful tools in the study of c-myc regulation and in the development of therapeutics that target the c-myc pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Combinatorial Chemistry Techniques / methods*
  • DNA Helicases
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism
  • Drug Design
  • Genes, myc*
  • Humans
  • Inhibitory Concentration 50
  • Ligands
  • Magnetic Resonance Spectroscopy*
  • Models, Molecular
  • Promoter Regions, Genetic*
  • Protein Conformation
  • Protein Structure, Tertiary
  • RNA-Binding Proteins
  • Repetitive Sequences, Amino Acid
  • Structure-Activity Relationship


  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • FUBP1 protein, human
  • Ligands
  • RNA-Binding Proteins
  • DNA Helicases