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

Overman, Jeroen, Fontaine, Frank, Moustaqil, Mehdi, Mittal, Deepak, Sierecki, Emma, Sacilotto, Natalia, Zuegg, Johannes, Robertson, Avril A. B., Holmes, Kelly, Salim, Angela A., Mamidyala, Sreeman, Butler, Mark S., Robinson, Ashley S., Lesieur, Emmanuelle, Johnston, Wayne, Alexandrov, Kirill, Black, Brian L., Hogan, Benjamin M., De Val, Sarah, Capon, Robert J., Carroll, Jason S., Bailey, Timothy L., Koopman, Peter, Jauch, Ralf, Smyth, Mark J., Cooper, Matthew A., Gambin, Yann and Francois, Mathias (2017) Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice. eLife, 6 . doi:10.7554/eLife.21221


Author Overman, Jeroen
Fontaine, Frank
Moustaqil, Mehdi
Mittal, Deepak
Sierecki, Emma
Sacilotto, Natalia
Zuegg, Johannes
Robertson, Avril A. B.
Holmes, Kelly
Salim, Angela A.
Mamidyala, Sreeman
Butler, Mark S.
Robinson, Ashley S.
Lesieur, Emmanuelle
Johnston, Wayne
Alexandrov, Kirill
Black, Brian L.
Hogan, Benjamin M.
De Val, Sarah
Capon, Robert J.
Carroll, Jason S.
Bailey, Timothy L.
Koopman, Peter
Jauch, Ralf
Smyth, Mark J.
Cooper, Matthew A.
Gambin, Yann
Francois, Mathias
Title Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
Journal name eLife   Check publisher's open access policy
ISSN 2050-084X
Publication date 2017-01-31
Year available 2017
Sub-type Article (original research)
DOI 10.7554/eLife.21221
Open Access Status DOI
Volume 6
Total pages 18
Place of publication Cambridge, United Kingdom
Publisher eLife Sciences Publications
Language eng
Subject 2800 Neuroscience
1300 Biochemistry, Genetics and Molecular Biology
2400 Immunology and Microbiology
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.
Keyword Small-Molecule Inhibitor
Vascular Development
Redundant Roles
Arterial Specification
Protein Expression
Lung-Cancer
Zebrafish
Gene
Cells
Lymphangiogenesis
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1008392
1048237
31471238
APP1011242
APP1025082
APP1048242
APP1059006
APP1078671
APP1111169
DP100140485
DP120101423
DP130102396
DP140100485
FT110100478
HL064658
HL089707
Institutional Status UQ

 
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