BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

Cell. 2011 Sep 16;146(6):904-17. doi: 10.1016/j.cell.2011.08.017. Epub 2011 Sep 1.

Abstract

MYC contributes to the pathogenesis of a majority of human cancers, yet strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have targeted MYC transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative coactivator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain proteins as regulatory factors for c-Myc. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of Myc-dependent target genes. In experimental models of multiple myeloma, a Myc-dependent hematologic malignancy, JQ1 produces a potent antiproliferative effect associated with cell-cycle arrest and cellular senescence. Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Azepines / chemistry
  • Azepines / pharmacology
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Discovery*
  • Humans
  • Mice
  • Multiple Myeloma / drug therapy*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Transcriptional Activation / drug effects
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • Triazoles
  • Benzodiazepines
  • molibresib

Associated data

  • GEO/GSE31365