Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

Abstract

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.DOI: http://dx.doi.org/10.7554/eLife.21221.001

AP-1 Imprints a Reversible Transcriptional Program of Senescent Cells

“…Pharmacological inhibition of TFs (see above for AP-1), signal transduction molecules, such as kinases or acetylases that converge in the activation of TFs, could represent a viable approach for manipulating the senescent phenotype in vivo 59 . Alternatively, small molecules that prevent TF-TF combinatorial interactions could also be envisioned 60 .…”

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

“…SOX18 homo- and heterodimerization can be inhibited by a small molecule, SM4 20–22 and by an FDA-approved beta blocker, propranolol 23 . Propranolol is produced as a 1:1 racemic mixture of R(+) and S(-) enantiomers.…”

Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy

“…As SOX18 TF functionality is dependent on or modulated by the presence of other co-binders, targeting of this GRN was an attractive anti-angiogenic strategy. The first step was to identify co-binders of SOX18 using ChIP-MS as a first line of screening [128]. These data have been coupled with a validation by AlphaScreen and single molecule fluorescence approaches that were optimised to scrutinise pairwise protein interactions in high throughput.…”

“…After identifying potential drug targets, Overman et al [128] screened a structurally diverse marine extract library for compounds that could interfere with SOX18-DNA interaction, using a fluorescence polarisation assay. From this screen, the authors identified the chemical space that was conserved between multiple compound hits.…”

“…To assess drug efficacy for the functional inhibition of TFs, biological systems should be studied during either embryogenesis or pathogenesis. Therefore, in the case of SOX18, embryonic vascular development and corresponding tumour-induced angiogenesis needed to be studied as relevant contexts [128]. First, a zebrafish model was used to investigate treatment-induced vascular malformation as a phenotypic readout of small molecule activity and compared to SOX18 genetic depletion.…”