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

eLife

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[1] Cancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom;Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, United States;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;Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia;Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia;School of Medicine, The University of Queensland, Herston, Australia;Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia;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;Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United Kingdom;

关键词: small molecules;    transcription factors;    protein protein interactions;    tumour angiogenesis;    gene expression;    Mouse;    Zebrafish;   

DOI  :  10.7554/eLife.21221

来源: publisher

【 摘 要 】

10.7554/eLife.21221.001Pharmacological 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

【 授权许可】

CC BY