AZD5153

A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies

Garrett W. Rhyasen, Maureen M. Hattersley, Yi Yao, Austin Dulak, Wenxian Wang, Philip Petteruti, Ian L. Dale, Scott Boiko, Tony Cheung, Jingwen Zhang, Shenghua Wen, Lillian Castriotta, Deborah Lawson, Michael Collins, Larry Bao, Miika J. Ahdesmaki, Graeme Walker, Greg O'Connor, Tammie C. Yeh, Alfred A. Rabow & 9 others Jonathan R. Dry, Corinne Reimer, Paul Lyne, Gordon Mills, Stephen E. Fawell, Michael J. Waring, Michael Zinda, Edwin Clark, Huawei Chen

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)2563-2574
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Hematologic Neoplasms
Neoplasms
Lymphoma, Large B-Cell, Diffuse
Multiple Myeloma
Heterografts
Acute Myeloid Leukemia
Chromatin
Biomarkers
Pharmacology
Gene Expression
Cell Line
Survival
Growth
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rhyasen, G. W., Hattersley, M. M., Yao, Y., Dulak, A., Wang, W., Petteruti, P., ... Chen, H. (2016). AZD5153: A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies. Molecular Cancer Therapeutics, 15(11), 2563-2574. https://doi.org/10.1158/1535-7163.MCT-16-0141

AZD5153 : A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies. / Rhyasen, Garrett W.; Hattersley, Maureen M.; Yao, Yi; Dulak, Austin; Wang, Wenxian; Petteruti, Philip; Dale, Ian L.; Boiko, Scott; Cheung, Tony; Zhang, Jingwen; Wen, Shenghua; Castriotta, Lillian; Lawson, Deborah; Collins, Michael; Bao, Larry; Ahdesmaki, Miika J.; Walker, Graeme; O'Connor, Greg; Yeh, Tammie C.; Rabow, Alfred A.; Dry, Jonathan R.; Reimer, Corinne; Lyne, Paul; Mills, Gordon; Fawell, Stephen E.; Waring, Michael J.; Zinda, Michael; Clark, Edwin; Chen, Huawei.

In: Molecular Cancer Therapeutics, Vol. 15, No. 11, 01.11.2016, p. 2563-2574.

Research output: Contribution to journalArticle

Rhyasen, GW, Hattersley, MM, Yao, Y, Dulak, A, Wang, W, Petteruti, P, Dale, IL, Boiko, S, Cheung, T, Zhang, J, Wen, S, Castriotta, L, Lawson, D, Collins, M, Bao, L, Ahdesmaki, MJ, Walker, G, O'Connor, G, Yeh, TC, Rabow, AA, Dry, JR, Reimer, C, Lyne, P, Mills, G, Fawell, SE, Waring, MJ, Zinda, M, Clark, E & Chen, H 2016, 'AZD5153: A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies', Molecular Cancer Therapeutics, vol. 15, no. 11, pp. 2563-2574. https://doi.org/10.1158/1535-7163.MCT-16-0141
Rhyasen, Garrett W. ; Hattersley, Maureen M. ; Yao, Yi ; Dulak, Austin ; Wang, Wenxian ; Petteruti, Philip ; Dale, Ian L. ; Boiko, Scott ; Cheung, Tony ; Zhang, Jingwen ; Wen, Shenghua ; Castriotta, Lillian ; Lawson, Deborah ; Collins, Michael ; Bao, Larry ; Ahdesmaki, Miika J. ; Walker, Graeme ; O'Connor, Greg ; Yeh, Tammie C. ; Rabow, Alfred A. ; Dry, Jonathan R. ; Reimer, Corinne ; Lyne, Paul ; Mills, Gordon ; Fawell, Stephen E. ; Waring, Michael J. ; Zinda, Michael ; Clark, Edwin ; Chen, Huawei. / AZD5153 : A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 11. pp. 2563-2574.
@article{ceeae25d14514b938607ea6ccb78ec52,
title = "AZD5153: A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies",
abstract = "The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies.",
author = "Rhyasen, {Garrett W.} and Hattersley, {Maureen M.} and Yi Yao and Austin Dulak and Wenxian Wang and Philip Petteruti and Dale, {Ian L.} and Scott Boiko and Tony Cheung and Jingwen Zhang and Shenghua Wen and Lillian Castriotta and Deborah Lawson and Michael Collins and Larry Bao and Ahdesmaki, {Miika J.} and Graeme Walker and Greg O'Connor and Yeh, {Tammie C.} and Rabow, {Alfred A.} and Dry, {Jonathan R.} and Corinne Reimer and Paul Lyne and Gordon Mills and Fawell, {Stephen E.} and Waring, {Michael J.} and Michael Zinda and Edwin Clark and Huawei Chen",
year = "2016",
month = "11",
day = "1",
doi = "10.1158/1535-7163.MCT-16-0141",
language = "English (US)",
volume = "15",
pages = "2563--2574",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - AZD5153

T2 - A novel bivalent BET bromodomain inhibitor highly active against hematologic malignancies

AU - Rhyasen, Garrett W.

AU - Hattersley, Maureen M.

AU - Yao, Yi

AU - Dulak, Austin

AU - Wang, Wenxian

AU - Petteruti, Philip

AU - Dale, Ian L.

AU - Boiko, Scott

AU - Cheung, Tony

AU - Zhang, Jingwen

AU - Wen, Shenghua

AU - Castriotta, Lillian

AU - Lawson, Deborah

AU - Collins, Michael

AU - Bao, Larry

AU - Ahdesmaki, Miika J.

AU - Walker, Graeme

AU - O'Connor, Greg

AU - Yeh, Tammie C.

AU - Rabow, Alfred A.

AU - Dry, Jonathan R.

AU - Reimer, Corinne

AU - Lyne, Paul

AU - Mills, Gordon

AU - Fawell, Stephen E.

AU - Waring, Michael J.

AU - Zinda, Michael

AU - Clark, Edwin

AU - Chen, Huawei

PY - 2016/11/1

Y1 - 2016/11/1

N2 - The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies.

AB - The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies.

UR - http://www.scopus.com/inward/record.url?scp=84995428342&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995428342&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-16-0141

DO - 10.1158/1535-7163.MCT-16-0141

M3 - Article

VL - 15

SP - 2563

EP - 2574

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 11

ER -