Haque, Mohammad Rashedul; (2011) Novel STAT3 Small-Molecule Inhibitors as Potential Anticancer Agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The STAT3 transcription factor plays a key role in a wide range of biological responses for cell survival and growth. Furthermore, the STAT3 signalling pathway has been found to be up-regulated in more than 70% of human tumours. To date STAT3 is a particularly promising molecular target for chemotherapeutic intervention, and a number of strategies are under investigation to selectively down-regulate STAT3 signalling in cancer cells to inhibit cell proliferation and promote cell death. In the molecularly-targeted drug discovery era, protein- protein interactions (PPIs) are emerging as an attractive class of novel targets. Proteins are associated with unique recognition patterns, thus targeting PPIs has the potential to develop highly selective drugs. In this context, blockade of STAT3 signalling through the modulation or inhibition of key protein-protein interactions is a valuable approach to inhibit STAT3 transcriptional activity. This research project has focused on the design and synthesis of small-molecule inhibitors of the STAT3:STAT3 protein interaction as a potential means to discover novel therapeutic agents using computational approaches such as virtual screening and structure-based design. In particular, a medicinal chemistry approach has been used to produce a novel library of potential PPI inhibitors based on a "hit" from an in silico screen. This library was screened using a primary PPI binding assay based on fluorescence polarisation (FP). Hits from this assay were screened in a MTS cell viability assay, a Trypan blue exclusion assay and a Luciferase reporter assay in STAT3-dependent (MDA-MB-231) and STAT3-null (A4) cell lines. Compounds with interesting activity in these assays were further studied in cellular assays to assess the extent of activity and specificity towards unphosphorylated STAT3, phosphorylated STAT3, phosphorylated STAT1, unphosphorylated STAT1 and the downstream mediators (i.e., Survivin, Bcl-XL and Cyclin D1) of STAT3 signalling. One compound identified, 60, has the ability to down-regulate IL-6 signalling at EC50 of 15 μM.

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