Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5605-9. doi: 10.1016/j.bmcl.2011.06.056. Epub 2011 Jun 30.


Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 μM), inhibited Stat3-Stat3 protein interactions (IC(50)=19 μM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 μM, respectively).

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Molecular Weight
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Salicylic Acid / chemical synthesis
  • Salicylic Acid / chemistry
  • Salicylic Acid / pharmacology*
  • Small Molecule Libraries
  • Stereoisomerism
  • Structure-Activity Relationship
  • src Homology Domains / drug effects*


  • Antineoplastic Agents
  • Ligands
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Small Molecule Libraries
  • Salicylic Acid