BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells

Oncotarget. 2015 Jul 10;6(19):17698-712. doi: 10.18632/oncotarget.4131.


The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.

Keywords: BET inhibitors; HEXIM1; OTX015; acute leukemias; c-MYC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Female
  • Fluorescent Antibody Technique
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Immunoblotting
  • Leukemia / pathology*
  • Male
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / drug effects
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / drug effects
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Proto-Oncogene Proteins c-myc / drug effects
  • RNA-Binding Proteins / drug effects
  • Real-Time Polymerase Chain Reaction
  • Transcription Factors / biosynthesis*
  • Transcription Factors / drug effects
  • Transcriptome


  • Acetanilides
  • Antineoplastic Agents
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Heterocyclic Compounds, 3-Ring
  • MYC protein, human
  • Nuclear Proteins
  • OTX015
  • Proto-Oncogene Proteins c-myc
  • RNA-Binding Proteins
  • Transcription Factors
  • Protein-Serine-Threonine Kinases