Small molecule compounds targeting DNA binding domain of STAT3 for inhibition of tumor growth and metastasis

Background Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and has important roles in multiple aspects of cancer aggressiveness.Thus targeting STAT3 promises to be an attractive strategy for treatment of advanced metastatic tumors.Although many STAT3 inhibitors targeting the SH2 domain have been reported, few have moved into clinical trials.Targeting the DNAbinding domain(DBD) of STAT3, however, has been avoided due to its ' undruggable' nature and potentially limited selectivity.Aim This study aims at developing effective and specific inhibitors targeting DNA binding domain of STAT3.Methods: This study reported an improved insilico approach targeting the DBD of STAT3 that resulted in a smallmolecule STAT3 inhibitor (inS354) and describe an extensive structure and activityguided hit optimization and mechanistic characterization effort, which led to identification of an improved lead compound (inS354A18) with increased specificity and pharmacological properties.Results: InS354A18 not only binds directly to the DBD and inhibits the DNAbinding activity of STAT3 both in vitro and in situ but also effectively inhibits the constitutive and interleukin6stimulated expression of STAT3 downstream target genes.InS354A18 is completely soluble in an oral formulation and effectively inhibits lung xenograft tumor growth and metastasis with little adverse effect on animals.Conclusion: InS354A18 may serve as a potential candidate for further development as anticancer therapeutics targeting the DBD of human STAT3 and DBD of transcription factors may not be ' undruggable' as previously thought.49-4