title: A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.
abstract: 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.
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MassachusettsAuthors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Marius S
authors.initials: MS
authors.lastname: Pop
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Garvie
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MassachusettsAuthors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Hartman
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Culyba
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Daniels
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Ronco
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MassachusettsAuthors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MassachusettsAuthors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
authors.affiliation: Authors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, MassachusettsAuthors' Affiliations: Dana Farber Cancer Institute, Boston; Broad Institute; Novartis Institute for Biomedical Research; Department of Biological Engineering; and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts levi_garraway@dfci.harvard.edu.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D054852:Small Molecule Libraries; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014227:Triazines / Q000008:administration & dosage*
chemical_list: D000814:Aniline Compounds; C000595239:BRD32048; D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D054852:Small Molecule Libraries; D014157:Transcription Factors; D014227:Triazines
references.citation: PLoS Negl Trop Dis. 2008 Mar 05;2(3):e190
references.pmid: 18320016
references.citation: Invasion Metastasis. 1989;9(3):192-208
references.pmid: 2722434
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18787-92
references.pmid: 20956335
references.citation: Curr Opin Chem Biol. 2007 Feb;11(1):74-82
references.pmid: 17169601
references.citation: Nat Chem Biol. 2010 Sep;6(9):667-73
references.pmid: 20711196
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D351-9
references.pmid: 17947324
references.citation: J Biol Chem. 2004 Apr 9;279(15):14909-16
references.pmid: 14747462
references.citation: Science. 2005 Oct 28;310(5748):644-8
references.pmid: 16254181
references.citation: Nature. 2010 Oct 14;467(7317):849-53
references.pmid: 20927104
references.citation: Mol Cell Biol. 2003 Sep;23(17):6243-54
references.pmid: 12917345
references.citation: J Comb Chem. 2007 Mar-Apr;9(2):245-53
references.pmid: 17348730
references.citation: Cancer Res. 2013 Aug 15;73(16):5110-9
references.pmid: 23774214
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4617-22
references.pmid: 19255428
references.citation: Cancer Res. 2010 Mar 1;70(5):2075-84
references.pmid: 20160028
references.citation: Bioorg Med Chem. 2012 Mar 15;20(6):1979-89
references.pmid: 22230199
references.citation: Oncogene. 2003 Feb 6;22(5):746-55
references.pmid: 12569367
references.citation: Oncogene. 2001 Sep 27;20(43):6215-24
references.pmid: 11593430
references.citation: Chem Biol. 2006 May;13(5):493-504
references.pmid: 16720270
references.citation: Mol Cell Biol. 1994 Dec;14(12):8058-70
references.pmid: 7969144
references.citation: Nucleic Acids Res. 2005 Nov 10;33(20):e175
references.pmid: 16284200
references.citation: Cancer Res. 2009 Oct 15;69(20):8102-10
references.pmid: 19789348
references.citation: PLoS One. 2011 Apr 29;6(4):e19343
references.pmid: 21559405
references.citation: Bioinformatics. 2004 Dec 12;20(18):3705-6
references.pmid: 15297296
references.citation: Nat Rev Cancer. 2002 Oct;2(10):740-9
references.pmid: 12360277
references.citation: Genes Dev. 2013 Mar 15;27(6):683-98
references.pmid: 23512661
references.citation: Chem Biol. 2010 May 28;17(5):471-82
references.pmid: 20534345
references.citation: Nucleic Acids Res. 2013 Jan 7;41(1):125-38
references.pmid: 23093599
references.citation: Proc Soc Exp Biol Med. 1999 Oct;222(1):9-28
references.pmid: 10510243
references.citation: Cancer Res. 2008 Sep 15;68(18):7541-9
references.pmid: 18794142
references.citation: FEBS Lett. 2003 Oct 9;553(1-2):104-8
references.pmid: 14550555
references.citation: Nat Protoc. 2006;1(5):2344-52
references.pmid: 17406478
references.citation: Nature. 2010 Dec 23;468(7327):1067-73
references.pmid: 20871596
references.citation: Cell. 2013 Apr 25;153(3):666-77
references.pmid: 23622249
references.citation: Curr Protoc Bioinformatics. 2008 Jun;Chapter 14:Unit 14.5
references.pmid: 18551413
references.citation: Nat Rev Drug Discov. 2002 Sep;1(9):727-30
references.pmid: 12209152
references.citation: Angew Chem Int Ed Engl. 2007;46(28):5352-5
references.pmid: 17568465
references.citation: Nature. 2007 Aug 2;448(7153):595-9
references.pmid: 17671502
references.citation: Bioorg Med Chem Lett. 2012 Sep 1;22(17):5714-20
references.pmid: 22832322
references.citation: Oncogene. 2010 Mar 25;29(12):1810-20
references.pmid: 20062082
references.citation: Nature. 2011 May 15;474(7351):403-6
references.pmid: 21572435
references.citation: Nature. 2005 Jul 7;436(7047):117-22
references.pmid: 16001072
references.citation: Oncotarget. 2012 Feb;3(2):172-82
references.pmid: 22383402
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: Mol Endocrinol. 2007 Aug;21(8):1835-46
references.pmid: 17505060
references.citation: Gene. 2005 Dec 19;363:1-14
references.pmid: 16202544
references.citation: J Biol Chem. 2002 Jun 7;277(23):20399-408
references.pmid: 11919190
references.citation: Biochim Biophys Acta. 2012 Aug;1826(1):1-12
references.pmid: 22425584
references.citation: Bioorg Med Chem Lett. 2013 Aug 1;23(15):4308-14
references.pmid: 23806553
references.citation: Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73
references.pmid: 20797855