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

TitlePharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
Authors
Issue Date2017
Citation
eLife, 2017, v. 6 How to Cite?
Abstract� Overman et al. 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.
Persistent Identifierhttp://hdl.handle.net/10722/253126
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorOverman, Jeroen-
dc.contributor.authorFontaine, Frank-
dc.contributor.authorMoustaqil, Mehdi-
dc.contributor.authorMittal, Deepak-
dc.contributor.authorSierecki, Emma-
dc.contributor.authorSacilotto, Natalia-
dc.contributor.authorZuegg, Johannes-
dc.contributor.authorRobertson, Avril A.B.-
dc.contributor.authorHolmes, Kelly-
dc.contributor.authorSalim, Angela A.-
dc.contributor.authorMamidyala, Sreeman-
dc.contributor.authorButler, Mark S.-
dc.contributor.authorRobinson, Ashley S.-
dc.contributor.authorLesieur, Emmanuelle-
dc.contributor.authorJohnston, Wayne-
dc.contributor.authorAlexandrov, Kirill-
dc.contributor.authorBlack, Brian L.-
dc.contributor.authorHogan, Benjamin M.-
dc.contributor.authorDe Val, Sarah-
dc.contributor.authorCapon, Robert J.-
dc.contributor.authorCarroll, Jason S.-
dc.contributor.authorBailey, Timothy L.-
dc.contributor.authorKoopman, Peter-
dc.contributor.authorJauch, Ralf-
dc.contributor.authorSmyth, Mark J.-
dc.contributor.authorCooper, Matthew A.-
dc.contributor.authorGambin, Yann-
dc.contributor.authorFrancois, Mathias-
dc.date.accessioned2018-05-11T05:38:40Z-
dc.date.available2018-05-11T05:38:40Z-
dc.date.issued2017-
dc.identifier.citationeLife, 2017, v. 6-
dc.identifier.urihttp://hdl.handle.net/10722/253126-
dc.description.abstract� Overman et al. 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.-
dc.languageeng-
dc.relation.ispartofeLife-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titlePharmacological targeting of the transcription factor SOX18 delays breast cancer in mice-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7554/eLife.21221-
dc.identifier.pmid28137359-
dc.identifier.scopuseid_2-s2.0-85011397522-
dc.identifier.volume6-
dc.identifier.spagenull-
dc.identifier.epagenull-
dc.identifier.eissn2050-084X-
dc.identifier.isiWOS:000393411100001-
dc.identifier.issnl2050-084X-

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