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

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).