A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein
Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, an...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2015
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| Online Access: | http://hdl.handle.net/1721.1/99462 |
| _version_ | 1826193977947193344 |
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| author | Pop, Marius S. Stransky, Nicolas Garvie, Colin W. Theurillat, Jean-Philippe Hartman, Emily C. Lewis, Timothy A. Zhong, Cheng Culyba, Elizabeth K. Lin, Fallon Daniels, Douglas S. Pagliarini, Raymond Ronco, Lucienne Koehler, Angela Nicole Garraway, Levi A. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Pop, Marius S. Stransky, Nicolas Garvie, Colin W. Theurillat, Jean-Philippe Hartman, Emily C. Lewis, Timothy A. Zhong, Cheng Culyba, Elizabeth K. Lin, Fallon Daniels, Douglas S. Pagliarini, Raymond Ronco, Lucienne Koehler, Angela Nicole Garraway, Levi A. |
| author_sort | Pop, Marius S. |
| collection | MIT |
| description | Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins. |
| first_indexed | 2024-09-23T09:48:39Z |
| format | Article |
| id | mit-1721.1/99462 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:48:39Z |
| publishDate | 2015 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/994622022-09-30T16:56:23Z A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein Pop, Marius S. Stransky, Nicolas Garvie, Colin W. Theurillat, Jean-Philippe Hartman, Emily C. Lewis, Timothy A. Zhong, Cheng Culyba, Elizabeth K. Lin, Fallon Daniels, Douglas S. Pagliarini, Raymond Ronco, Lucienne Koehler, Angela Nicole Garraway, Levi A. Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Koehler, Angela Nicole Members of the ETS transcription factor family have been implicated in several cancers, where they are often dysregulated by genomic derangement. ETS variant 1 (ETV1) is an ETS factor gene that undergoes chromosomal translocation in prostate cancers and Ewing sarcomas, amplification in melanomas, and lineage dysregulation in gastrointestinal stromal tumors. Pharmacologic perturbation of ETV1 would be appealing in these cancers; however, oncogenic transcription factors are often deemed “undruggable” by conventional methods. Here, we used small-molecule microarray screens to identify and characterize drug-like compounds that modulate the biologic function of ETV1. We identified the 1,3,5-triazine small molecule BRD32048 as a top candidate ETV1 perturbagen. BRD32048 binds ETV1 directly, modulating both ETV1-mediated transcriptional activity and invasion of ETV1-driven cancer cells. Moreover, BRD32048 inhibits p300-dependent acetylation of ETV1, thereby promoting its degradation. These results point to a new avenue for pharmacologic ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins. National Cancer Institute (U.S.) (Initiative for Chemical Genetics Contract N01-CO-12400) National Cancer Institute (U.S.) (Cancer Target Discovery and Development Network RC2 CA148399) 2015-10-27T12:40:46Z 2015-10-27T12:40:46Z 2014-04 2014-04 Article http://purl.org/eprint/type/JournalArticle 1535-7163 1538-8514 http://hdl.handle.net/1721.1/99462 Pop, M. S., N. Stransky, C. W. Garvie, J.-P. Theurillat, E. C. Hartman, T. A. Lewis, C. Zhong, et al. “A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein.” Molecular Cancer Therapeutics 13, no. 6 (April 15, 2014): 1492–1502. en_US http://dx.doi.org/10.1158/1535-7163.mct-13-0689 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Pop, Marius S. Stransky, Nicolas Garvie, Colin W. Theurillat, Jean-Philippe Hartman, Emily C. Lewis, Timothy A. Zhong, Cheng Culyba, Elizabeth K. Lin, Fallon Daniels, Douglas S. Pagliarini, Raymond Ronco, Lucienne Koehler, Angela Nicole Garraway, Levi A. A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title | A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title_full | A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title_fullStr | A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title_full_unstemmed | A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title_short | A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein |
| title_sort | small molecule that binds and inhibits the etv1 transcription factor oncoprotein |
| url | http://hdl.handle.net/1721.1/99462 |
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