Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that plays a key role in regulating gene expression leading to cellular processes such as cell proliferation, differentiation and apoptosis. Constitutive activation of STAT3 has been detected at a high frequency in diverse human cancers. Inhibiting STAT3 results in decreased tumor growth and improvement in animal survival. Hence, STAT3 is considered a potential drug development target for novel anticancer therapeutics. STAT3 has been under intense investigation for many years, however no drug targeting it has been approved. In our search for novel potent STAT3 inhibitors, we have discovered a series of new compounds that interrupt STAT3-DNA binding at low micro molar concentrations. Subsequently, pharmacophore-based 3D QSAR studies were carried out to determine the role of functional groups and conformations required for activity. Docking and MM-GBSA-based refinement procedures suggested that these compounds bind to a DNA binding site of the STAT3 DNA binding domain, unlike many STAT3 inhibitors that are thought to bind to the SH2 domain. In the present study, we describe the biological testing, computational modeling, rational design and synthesis as well as SAR studies of the novel STAT3 inhibitors.

Novel STAT3 inhibitors: Synthesis, biological evaluation, SAR and modeling studies

247th National Meeting (2014)

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