A Small Molecule that Binds and Inhibits the ETV1 Transcription Factor Oncoprotein

Author(s)

Marius C. Pop, Dana Farber Cancer Institute
Nicolas Stransky, Broad Institute of MIT and Harvard
Colin W. Garvie, Broad Institute of MIT and Harvard
Jean-Philippe Theurillat, Dana Farber Cancer Institute
Emily C. Hartman, Broad Institute of MIT and Harvard
Timothy A. Lewis, Broad Institute of MIT and Harvard
Cheng Zhong, Broad Institute of MIT and Harvard
Elizabeth K. Culyba, Broad Institute of MIT and Harvard
Fallon Lin, Novartis Institute for Biomedical Research
Douglas S. Daniels, University of DaytonFollow
Raymond Pagliarini, Novartis Institute for Biomedical Research
Lucienne Ronco, Broad Institute of MIT and Harvard
Angela N. Koehler, Broad Institute of MIT and Harvard
Levi A. Garraway, Dana Farber Cancer Institute

Document Type

Article

Publication Date

4-15-2014

Publication Source

Molecular Cancer Therapeutics

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's 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 (SMM) screens to identify and characterize drug-like compounds that modulate the biological 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 pharmacological ETV1 inhibition and may inform a general means to discover small molecule perturbagens of transcription factor oncoproteins.

Inclusive pages

1492-1502

ISBN/ISSN

1535-7163

Document Version

Postprint

Comments

The document available for download is the authors' accepted manuscript, provided in compliance with the publisher's policy on self-archiving. Permission documentation is on file.

Copyright

Copyright © 2014 American Association for Cancer Research

Publisher

American Association for Cancer Research

Volume

13

Peer Reviewed

yes

Issue

6

Sponsoring Agency

National Cancer Institute's Initiative for Chemical Genetics (ICG) under Contract No. N01-CO-12400, and the Cancer Target Discovery and Development (CTD2) Network, under RC2 CA148399

eCommons Citation

Pop, Marius C.; 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 N.; and Garraway, Levi A., "A Small Molecule that Binds and Inhibits the ETV1 Transcription Factor Oncoprotein" (2014). Chemistry Faculty Publications. 96.
https://ecommons.udayton.edu/chm_fac_pub/96