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Mol Cancer Ther DOI:10.1158/1535-7163.MCT-13-0689

A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein.

Publication TypeJournal Article
Year of Publication2014
AuthorsPop, MS, Stransky, N, Garvie, CW, Theurillat, J-P, Hartman, EC, Lewis, TA, Zhong, C, Culyba, EK, Lin, F, Daniels, DS, Pagliarini, R, Ronco, L, Koehler, AN, Garraway, LA
JournalMol Cancer Ther
Date Published2014 Jun
KeywordsAniline Compounds, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Male, Molecular Targeted Therapy, Neoplasms, Promoter Regions, Genetic, Prostatic Neoplasms, Small Molecule Libraries, Surface Plasmon Resonance, Transcription Factors, Triazines

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.


Alternate JournalMol. Cancer Ther.
PubMed ID24737027
PubMed Central IDPMC4154495
Grant ListRC2 CA148399 / CA / NCI NIH HHS / United States
RC2CA148399 / CA / NCI NIH HHS / United States
P01 CA163222 / CA / NCI NIH HHS / United States
U01 CA162148 / CA / NCI NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States