Disruption of transcriptionally active Stat3 dimers with non-phosphorylated, salicylic acid-based small molecules: potent in vitro and tumor cell activities

Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that relays signals from receptors in the plasma membrane directly to the nucleus, and is routinely hyperactivated in many human cancers and diseases.[1] Regarded as an oncogene, Stat3 is well-recognized as a master regulator of cellular events that lead to the cancer phenotype, making this protein viable target for molecular therapeutic design.[2] Stat3 inhibitors have included peptides,[3–4] peptidomimetics,[5–9] small molecules[10–14] and metal complexes.[15] Despite significant advances in Stat3 inhibition,[1] truly potent (in vivo), isoform-selective, small molecule Stat3 agents have not been readily forthcoming; this is likely due in part to the challenge of disrupting protein–protein interactions.[16]