title: 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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Overman
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Fontaine
authors.affiliation: 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.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Moustaqil
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Mittal
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Sierecki
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United Kingdom.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sacilotto
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Avril A B
authors.initials: AAB
authors.lastname: Robertson
authors.affiliation: Cancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Holmes
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Salim
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Sreeman
authors.initials: S
authors.lastname: Mamidyala
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Butler
authors.affiliation: Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, United States.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Robinson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lesieur
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Wayne
authors.initials: W
authors.lastname: Johnston
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Kirill
authors.initials: K
authors.lastname: Alexandrov
authors.affiliation: Cardiovascular Research Institute, The University of California, San Francisco, San Francisco, United States.
authors.forename: Brian L
authors.identifier: https://orcid.org/0000-0002-6664-8913
authors.initials: BL
authors.lastname: Black
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hogan
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: De Val
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
authors.affiliation: Cancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom.
authors.forename: Jason S
authors.identifier: https://orcid.org/0000-0003-3643-0080
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Bailey
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.affiliation: 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.
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: 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.
authors.forename: Yann
authors.identifier: https://orcid.org/0000-0001-7378-8976
authors.initials: Y
authors.lastname: Gambin
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Mathias
authors.identifier: https://orcid.org/0000-0002-9846-6882
authors.initials: M
authors.lastname: Francois
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D055592:Biophysical Phenomena; D001808:Blood Vessels / Q000196:embryology; D001943:Breast Neoplasms / Q000517:prevention & control*; D004195:Disease Models, Animal; D023281:Genomics; D051379:Mice; D040901:Proteomics; D055760:SOXF Transcription Factors / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects*; D016896:Treatment Outcome; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D055760:SOXF Transcription Factors; C490653:Sox18 protein, mouse; C526282:Sox18 protein, zebrafish; D029961:Zebrafish Proteins
keywords: biochemistry; developmental biology; gene expression; mouse; protein protein interactions; small molecules; stem cells; transcription factors; tumour angiogenesis; zebrafish