Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice
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 i...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2017-01-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/21221 |
| _version_ | 1827874612729348096 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Jeroen Overman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T16:54:20Z |
| format | Article |
| id | doaj.art-1f3cf6e6ad3345a2bb95b0d0d5a753be |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-12T16:54:20Z |
| publishDate | 2017-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1f3cf6e6ad3345a2bb95b0d0d5a753be2023-08-08T09:23:19ZengeLife Sciences Publications LtdeLife2050-084X2017-01-01610.7554/eLife.21221Pharmacological targeting of the transcription factor SOX18 delays breast cancer in miceJeroen Overman0Frank Fontaine1Mehdi Moustaqil2Deepak Mittal3Emma Sierecki4Natalia Sacilotto5Johannes Zuegg6Avril AB Robertson7Kelly Holmes8Angela A Salim9Sreeman Mamidyala10Mark S Butler11Ashley S Robinson12Emmanuelle Lesieur13Wayne Johnston14Kirill Alexandrov15Brian L Black16https://orcid.org/0000-0002-6664-8913Benjamin M Hogan17Sarah De Val18Robert J Capon19Jason S Carroll20https://orcid.org/0000-0003-3643-0080Timothy L Bailey21Peter Koopman22Ralf Jauch23Matthew A Cooper24Yann Gambin25https://orcid.org/0000-0001-7378-8976Mathias Francois26https://orcid.org/0000-0002-9846-6882Institute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, AustraliaImmunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, AustraliaLudwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United KingdomInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaCancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United KingdomInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaCardiovascular Research Institute, The University of California, San Francisco, San Francisco, United StatesInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaCardiovascular Research Institute, The University of California, San Francisco, San Francisco, United StatesInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaLudwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, The University of Oxford, Oxford, United KingdomInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaCancer Research UK, The University of Cambridge, Li Ka Shing Centre, Cambridge, United KingdomInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaGenome 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, ChinaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, Australia; Single Molecule Science, Lowy Cancer Research Centre, The University of New South Wales, Sydney, AustraliaInstitute for Molecular Bioscience, The University of Queensland, Brisbane, AustraliaPharmacological 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.https://elifesciences.org/articles/21221small moleculestranscription factorsprotein protein interactionstumour angiogenesisgene expression |
| spellingShingle | 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 Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice eLife small molecules transcription factors protein protein interactions tumour angiogenesis gene expression |
| title | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
| title_full | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
| title_fullStr | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
| title_full_unstemmed | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
| title_short | Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice |
| title_sort | pharmacological targeting of the transcription factor sox18 delays breast cancer in mice |
| topic | small molecules transcription factors protein protein interactions tumour angiogenesis gene expression |
| url | https://elifesciences.org/articles/21221 |
| work_keys_str_mv | AT jeroenoverman pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT frankfontaine pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT mehdimoustaqil pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT deepakmittal pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT emmasierecki pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT nataliasacilotto pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT johanneszuegg pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT avrilabrobertson pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT kellyholmes pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT angelaasalim pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT sreemanmamidyala pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT marksbutler pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT ashleysrobinson pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT emmanuellelesieur pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT waynejohnston pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT kirillalexandrov pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT brianlblack pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT benjaminmhogan pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT sarahdeval pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT robertjcapon pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT jasonscarroll pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT timothylbailey pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT peterkoopman pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT ralfjauch pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT matthewacooper pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT yanngambin pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice AT mathiasfrancois pharmacologicaltargetingofthetranscriptionfactorsox18delaysbreastcancerinmice |