Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein–protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors.

• Docking
• pharmacophore model
• STAT3
• virtual screening

Acknowledgements

Many thanks are due to Prof. Maurizio Botta for using PHASE and GLIDE program in his computational laboratory (University of Siena, Italy) and warmly thank Prof.ssa Daniela Barlocco for the helpful discussion.

Declaration of interest

The authors report no declarations of interest. The authors acknowledge the Italian Ministero dell’Università e della Ricerca (MIUR), under the National Interest Research Projects framework (PRIN_2010_5YY2HL) for the financial support.

Supplementary material available online

Supplementary Figure S1 and Tables S1-S2