Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design

J Med Chem. 2013 Jun 13;56(11):4402-12. doi: 10.1021/jm400080c. Epub 2013 May 16.

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

Publication types

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

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Computer Simulation
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Fluorescence Polarization
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Binding
  • Protein Multimerization
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / chemistry
  • STAT3 Transcription Factor / metabolism
  • Small Molecule Libraries / chemistry
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology
  • Transplantation, Heterologous
  • Tumor Burden / drug effects
  • src Homology Domains

Substances

  • 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide
  • Aminopyridines
  • Antineoplastic Agents
  • STAT3 Transcription Factor
  • Small Molecule Libraries
  • Sulfonamides