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 Roberts & 5 others Maurits Kleijnen, Jason J. Witherington, Nigel J. Parr, Rab K. Prinjha, Anastasios Karadimitris

Research output: Contribution to journalArticle

100 Citations (Scopus)

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

Fingerprint

Positive Transcriptional Elongation Factor B
Cell proliferation
Cell Proliferation
Molecules
Hematologic Neoplasms
Multiple Myeloma
Heterografts
Chromatin
Up-Regulation
Apoptosis
Testing
GSK525762A
GSK1210151A
Proteins
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Chaidos, A., Caputo, V., Gouvedenou, K., Liu, B., Marigo, I., Chaudhry, M. S., ... 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

Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. / Chaidos, Aristeidis; Caputo, Valentina; Gouvedenou, Katerina; Liu, Binbin; Marigo, Ilaria; Chaudhry, Mohammed Suhail; Rotolo, Antonia; Tough, David F.; Smithers, Nicholas N.; Bassil, Anna K.; Chapman, Trevor D.; Harker, Nicola R.; Barbash, Olena; Tummino, Peter; Al-Mahdi, Niam; Haynes, Andrea C.; Cutler, Leanne; Le, BaoChau; Rahemtulla, Amin; Roberts, Irene; Kleijnen, Maurits; Witherington, Jason J.; Parr, Nigel J.; Prinjha, Rab K.; Karadimitris, Anastasios.

In: Blood, Vol. 123, No. 5, 30.01.2014, p. 697-705.

Research output: Contribution to journalArticle

Chaidos, A, Caputo, V, Gouvedenou, K, Liu, B, Marigo, I, Chaudhry, MS, Rotolo, A, Tough, DF, Smithers, NN, Bassil, AK, Chapman, TD, Harker, NR, Barbash, O, Tummino, P, Al-Mahdi, N, Haynes, AC, Cutler, L, Le, B, Rahemtulla, A, Roberts, I, Kleijnen, M, Witherington, JJ, Parr, NJ, Prinjha, RK & Karadimitris, A 2014, 'Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762', Blood, vol. 123, no. 5, pp. 697-705. https://doi.org/10.1182/blood-2013-01-478420
Chaidos, Aristeidis ; Caputo, Valentina ; Gouvedenou, Katerina ; Liu, Binbin ; Marigo, Ilaria ; Chaudhry, Mohammed Suhail ; Rotolo, Antonia ; Tough, David F. ; Smithers, Nicholas N. ; Bassil, Anna K. ; Chapman, Trevor D. ; Harker, Nicola R. ; Barbash, Olena ; Tummino, Peter ; Al-Mahdi, Niam ; Haynes, Andrea C. ; Cutler, Leanne ; Le, BaoChau ; Rahemtulla, Amin ; Roberts, Irene ; Kleijnen, Maurits ; Witherington, Jason J. ; Parr, Nigel J. ; Prinjha, Rab K. ; Karadimitris, Anastasios. / Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. In: Blood. 2014 ; Vol. 123, No. 5. pp. 697-705.
@article{f8360c7182ee415c9f2c7ac4a4315c64,
title = "Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762",
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.",
author = "Aristeidis Chaidos and Valentina Caputo and Katerina Gouvedenou and Binbin Liu and Ilaria Marigo and Chaudhry, {Mohammed Suhail} and Antonia Rotolo and Tough, {David F.} and Smithers, {Nicholas N.} and Bassil, {Anna K.} and Chapman, {Trevor D.} and Harker, {Nicola R.} and Olena Barbash and Peter Tummino and Niam Al-Mahdi and Haynes, {Andrea C.} and Leanne Cutler and BaoChau Le and Amin Rahemtulla and Irene Roberts and Maurits Kleijnen and Witherington, {Jason J.} and Parr, {Nigel J.} and Prinjha, {Rab K.} and Anastasios Karadimitris",
year = "2014",
month = "1",
day = "30",
doi = "10.1182/blood-2013-01-478420",
language = "English",
volume = "123",
pages = "697--705",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

TY - JOUR

T1 - Potentantimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762

AU - Chaidos, Aristeidis

AU - Caputo, Valentina

AU - Gouvedenou, Katerina

AU - Liu, Binbin

AU - Marigo, Ilaria

AU - Chaudhry, Mohammed Suhail

AU - Rotolo, Antonia

AU - Tough, David F.

AU - Smithers, Nicholas N.

AU - Bassil, Anna K.

AU - Chapman, Trevor D.

AU - Harker, Nicola R.

AU - Barbash, Olena

AU - Tummino, Peter

AU - Al-Mahdi, Niam

AU - Haynes, Andrea C.

AU - Cutler, Leanne

AU - Le, BaoChau

AU - Rahemtulla, Amin

AU - Roberts, Irene

AU - Kleijnen, Maurits

AU - Witherington, Jason J.

AU - Parr, Nigel J.

AU - Prinjha, Rab K.

AU - Karadimitris, Anastasios

PY - 2014/1/30

Y1 - 2014/1/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84897024898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84897024898&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-01-478420

DO - 10.1182/blood-2013-01-478420

M3 - Article

VL - 123

SP - 697

EP - 705

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -