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Development of small-molecule transforming growth factor beta antagonists


Transforming growth factor beta (TGFβ) is a multi-functional cytokine that regulates a wide variety of cellular processes, such as proliferation, differentiation and apoptosis. The role of TGFβ in breast cancer is complex. In the early stages of the disease TGFβ functions as a tumour suppressor, but later the protein switches to a prometastatic factor, suggesting that the inhibition of TGFβ activity may be of benefit in the treatment of stage IV metastatic disease. There is much interest at the present time in the development of strategies to inhibit the TGFβ signalling pathway for the treatment of metastatic cancer and other diseases.

We are using an in silico approach to identify small molecules capable of disrupting the TGFβ signalling pathway. In particular, we are searching for compounds with the ability to bind to the same site on the type II receptor (TβR-II) as TGFβ itself, thus preventing recruitment of the type I receptor, effectively blocking the ensuing signalling cascade.


Molecular docking was performed using the commercially available docking program FlexX [1]. We attempted to dock 250,251 molecules from the NCI compound library against the extracellular domain of TβR-II, coordinates for which were taken from a crystal structure of the TGFβ3:TβR-II complex (Protein Data Bank accession number 1KTZ [2]). The consensus scoring function embedded within the software was used to assign each compound with a score, allowing them to be ranked, such that the highest ranking compounds could be prioritised for in vitro assessment.

The ability of the compounds to inhibit TGFβ signalling was tested in a cell-based reporter assay [3]. Any compounds shown to bring about a reduction in TGFβ signalling were taken forward for IC50 determination, performed in tandem with an MTT cell viability assay.


From the NCI compound database, a total of 219,567 molecules were successfully docked and scored by FlexX. Eighteen of the highest-ranking 40 compounds were obtained from the NCI Developmental Therapeutics Program and assessed for their ability to inhibit TGFβ signalling. One of these compounds was shown to inhibit TGFβ signalling without displaying any significant cytotoxicity.


We have discovered a novel, small molecule capable of inhibiting TGFβ signal transduction. Our current work is focused on identifying the mode of action of this molecule and on the exploration of the surrounding chemical space, with a view to discovering more potent compounds and developing structure–activity relationships.


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The authors would like to thank Breast Cancer Campaign for funding and the NCI Developmental Therapeutics Program for supplying the small molecules.

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Warner, D., Sessions, R., Dawbarn, D. et al. Development of small-molecule transforming growth factor beta antagonists. Breast Cancer Res 8 (Suppl 2), P37 (2006).

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