eLife (Jan 2017)
Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
- Jeroen Overman,
- Frank Fontaine,
- Mehdi Moustaqil,
- Deepak Mittal,
- Emma Sierecki,
- Natalia Sacilotto,
- Johannes Zuegg,
- Avril AB Robertson,
- Kelly Holmes,
- Angela A Salim,
- Sreeman Mamidyala,
- Mark S Butler,
- Ashley S Robinson,
- Emmanuelle Lesieur,
- Wayne Johnston,
- Kirill Alexandrov,
- Brian L Black,
- Benjamin M Hogan,
- Sarah De Val,
- Robert J Capon,
- Jason S Carroll,
- Timothy L Bailey,
- Peter Koopman,
- Ralf Jauch,
- Matthew A Cooper,
- Yann Gambin,
- Mathias Francois
Affiliations
- Jeroen Overman
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Frank Fontaine
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Mehdi Moustaqil
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, Australia
- Deepak Mittal
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
- Emma Sierecki
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, Australia
- Natalia Sacilotto
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United Kingdom
- Johannes Zuegg
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Avril AB Robertson
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Kelly Holmes
- Cancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom
- Angela A Salim
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Sreeman Mamidyala
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Mark S Butler
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Ashley S Robinson
- Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, United States
- Emmanuelle Lesieur
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Wayne Johnston
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Kirill Alexandrov
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Brian L Black
- ORCiD
- Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, United States
- Benjamin M Hogan
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Sarah De Val
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United Kingdom
- Robert J Capon
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Jason S Carroll
- ORCiD
- Cancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom
- Timothy L Bailey
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Peter Koopman
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Ralf Jauch
- Genome Regulation Laboratory, Drug Discovery Pipeline, CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Guangzhou Medical University, Guangzhou, China
- Matthew A Cooper
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Yann Gambin
- ORCiD
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, Australia
- Mathias Francois
- ORCiD
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- DOI
- https://doi.org/10.7554/eLife.21221
- Journal volume & issue
-
Vol. 6
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.
Keywords
- small molecules
- transcription factors
- protein protein interactions
- tumour angiogenesis
- gene expression
