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

Marius S Pop1, Nicolas Stransky2, Colin W Garvie2

  • 1Authors' 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.

Molecular Cancer Therapeutics
|April 17, 2014
PubMed

Insights

Researchers identified a small molecule, BRD32048, that targets the ETS variant 1 (ETV1) transcription factor. This discovery offers a new strategy for inhibiting ETV1 in cancers where it is dysregulated, potentially overcoming the "undruggable" challenge.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The ETS transcription factor family, including ETS variant 1 (ETV1), is frequently dysregulated in various cancers.
  • ETV1 alterations are observed in prostate cancers, Ewing sarcomas, melanomas, and gastrointestinal stromal tumors.
  • Targeting oncogenic transcription factors like ETV1 is challenging due to their 'undruggable' nature.

Purpose of the Study:

  • To identify and characterize small molecules that modulate the biological function of ETV1.
  • To explore novel pharmacologic strategies for inhibiting ETV1 in cancer treatment.

Main Methods:

  • Utilized small-molecule microarray screens to discover ETV1 modulators.
  • Investigated the direct binding of identified compounds to ETV1.
  • Assessed the impact of compounds on ETV1-mediated transcription and cancer cell invasion.
  • Examined the effect of compounds on ETV1 acetylation and degradation.

Main Results:

  • Identified BRD32048, a 1,3,5-triazine small molecule, as a potent ETV1 perturbagen.
  • BRD32048 directly binds to ETV1, reducing its transcriptional activity and inhibiting invasion in ETV1-driven cancer cells.
  • BRD32048 promotes ETV1 degradation by inhibiting p300-dependent acetylation.

Conclusions:

  • BRD32048 represents a promising new approach for pharmacologic ETV1 inhibition in cancer.
  • This study provides a generalizable method for discovering small molecule inhibitors of transcription factor oncoproteins.

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