Abstract

Transcription factors are proteins that bind DNA at specific regulatory motifs to activate or inhibit gene expression. Around 1500 genes are thought to encode transcriptional regulators that range from house-keeping transcription factors, to factors that are spatially, temporally or sequentially expressed during development, cell renewal or differentiation. Disruption of their expression or activity may result in deregulated cell integrity or homeostasis leading to pathologies including cancer. Transcription factors account for around 20% of all currently identified oncogenes and are also clearly associated with non-oncogene addiction. Transcription factors are often considered “undruggable” as they are generally ligandless and are frequently regulated through protein-protein interactions. Here I will present our experience with cell-based phenotypic screens where we have identified inhibitors of specific transcription factor activation. Using a cell-based approach coupled with chemo-proteomics we were able to successfully discover hit series of compounds that were amenable for drug development and were also able to deconvolute their cellular targets. I will present our experience and learnings from the discovery of inhibitors of oncogenic beta-catenin activation by the WNT-pathway and also inhibitors of HSF1 activation, a transcription factor that regulates the cellular and oncogenic stress response associated with non-oncogene addiction. Despite the challenges associated with targeting transcription factors and deconvoluting hits from cell-based screens a phenotypic strategy can successfully discover hit matter that can not only be developed as potent tool compounds, but also can be progressed to clinical candidates.