Screening for small molecule inhibitors of a transcription factor target implicated in cancer

The Northern Institute for Cancer Research (NICR) and CRT have recently collaborated on a screening campaign in order to initiate a drug discovery program to develop a small molecule inhibitor of a transcription factor implicated in cancer. This target has no screening precedent in the literature. The transcription factor target was elected to be screened using a biophysical fluorescence polarisation (FP) assay rather than through a more traditional method of a phenotypic or reporter gene cell assay. The FP assay was developed at NICR, using a fluorescent labelled oligo duplex. The assay was then successfully transferred and miniaturised to enable screening within a low volume 384 well format at CRT. An HTS campaign was then run against 150,000 compounds, approximately half of which were newly acquired and selected on the basis of novelty in 3D shape.
We are aware that our chemical library contains compounds with potential redox properties that can interfere non-specifically with enzyme activity. Since redox activity of compounds is a concern for compound optimisation, all HTS active compounds were counter-screened for their ability to generate H2O2 in the presence of DTT. This poster will describe the process carried out at NICR and CRT to develop the biochemical assay, including optimisation of the labelled oligo duplex, the screening cascade and early screening results.

Poster presented by Cristina Alli at ELRIG Drug Discovery 2015 (Telford, UK)

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