Identification of novel STAT3 inhibitors


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B.Piku Basu1, Giovanna Zinzalla1, Rashedul Haque1, Dyeison Antonow1, Andy Wilderspin1, Fyeza Hasan2, Daniel Morgenstern2, John Anderson2, David E. Thurston1

1The School of Pharmacy, University of London, UK, 2The Institute of Child Health, London, UK

Abstract

Background

STAT3 is a member of the signal transducers and activators of transcription (STAT) family. The transcription factor becomes activated through phosphorylation on tyrosine in response to a variety of stimuli such as EGF, IL-6, PDGF, IL-2 and G-CSF. It then dimerises and translocates to the nucleus in order to modulate the transcription of various genes. STAT3 has been identified as a cancer target as it is persistently activated in many cancers and appears to play an important role in tumour immune escape. No STAT3 specific inhibitors have thus far been developed for use in humans.

Method

In silico and medicinal chemistry approaches were used to develop 26 candidate compounds which showed potential binding to the STAT3 phosphorylation site. These compounds were then assessed for biological activity using a step-wise in vitro screening process. Effects of the compounds on tumour cell survival were assessed using MTS and trypan blue exclusion assays. Comparative analysis of a STAT3-dependent breast cancer cell line (MDA-MB231) with STAT3-null A4 cells allowed identification of compounds with apparent STAT3-specific inhibitory activity. Compounds that exerted STAT3 specific inhibitory effects on tumour cells were assessed for their ability to disrupt STAT3 transcriptional activity using a stable STAT3-luciferase Hela reporter cell line.

Results

From extensive in vitro screening of test compounds, three novel compounds have been identified that cause STAT3 specific inhibition in STAT3 dependent cancer cell lines. These compounds specifically inhibit STAT3 transcriptional activity with apparent IC50 values of less than 30μM and this has been correlated to abrogation of STAT3 phosphorylation. Interestingly, the compounds have a predominantly cytostatic rather than cytotoxic effect on the cancer cells.

Conclusion

The new compounds are currently being assessed for preliminary in vivo activity. It is hoped that further modification of these compounds will produce derivatives with enhanced IC50 values and improved bioavailability.

From extensive in vitro screening of test compounds, three novel compounds have been identified that cause STAT3 specific inhibition in STAT3 dependent cancer cell lines. These compounds specifically inhibit STAT3 transcriptional activity with apparent IC50 values of less than 30μM and this has been correlated to abrogation of STAT3 phosphorylation. Interestingly, the compounds have a predominantly cytostatic rather than cytotoxic effect on the cancer cells.