Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762

Aristeidis Chaidos, Valentina Caputo, Katerina Gouvedenou, Binbin Liu, Ilaria Marigo, Mohammed Suhail Chaudhry, Antonia Rotolo, David F. Tough, Nicholas N. Smithers, Anna K. Bassil, Trevor D. Chapman, Nicola R. Harker, Olena Barbash, Peter Tummino, Niam Al-Mahdi, Andrea C. Haynes, Leanne Cutler, BaoChau Le, Amin Rahemtulla, Irene RobertsMaurits Kleijnen, Jason J. Witherington, Nigel J. Parr, Rab K. Prinjha, Anastasios Karadimitris

Research output: Contribution to journalArticle

Abstract

The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.

Original languageEnglish
Pages (from-to)697-705
Number of pages9
JournalBlood
Volume123
Issue number5
DOIs
Publication statusPublished - Jan 30 2014

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Chaidos, A., Caputo, V., Gouvedenou, K., Liu, B., Marigo, I., Chaudhry, M. S., Rotolo, A., Tough, D. F., Smithers, N. N., Bassil, A. K., Chapman, T. D., Harker, N. R., Barbash, O., Tummino, P., Al-Mahdi, N., Haynes, A. C., Cutler, L., Le, B., Rahemtulla, A., ... Karadimitris, A. (2014). Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood, 123(5), 697-705. https://doi.org/10.1182/blood-2013-01-478420