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. RabowJonathan R. Dry, Corinne Reimer, Paul Lyne, Gordon B. Mills, Stephen E. Fawell, Michael J. Waring, Michael Zinda, Edwin Clark, Huawei Chen

    Research output: Contribution to journalArticle

    49 Scopus citations

    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 2016

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Rhyasen, G. W., Hattersley, M. M., Yao, Y., Dulak, A., Wang, W., Petteruti, P., Dale, I. L., Boiko, S., Cheung, T., Zhang, J., Wen, S., Castriotta, L., Lawson, D., Collins, M., Bao, L., Ahdesmaki, M. J., Walker, G., O'Connor, G., Yeh, T. C., ... 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