A Small Molecule That Binds and Inhibits the ETV1 Transcription Factor Oncoprotein
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Author(s)
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.
Date Issued
April 2014
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research
Citation
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.
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1158/1535-7163.mct-13-0689
