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Lookup NU author(s): Professor Mike Waring
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
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 (AML), Multiple Myeloma (MM), and Diffuse Large B-cell Lymphoma (DLBCL). The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly impacts 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 report establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides rationale for clinical development in hematologic malignancies.
Author(s): Rhyasen GW, Hattersley M, Yao Y, Dulak A, Wang W, Petteruti P, Dale I, Boiko S, Cheung T, Zhang J, Wen S, Castriotta L, Lawson D, Collins M, Bao L, Ahdesmaki MJ, Walker G, O'Connor G, Yeh T, Rabow AA, Dry J, Reimer C, Lyne P, Mills GB, Fawell S, Waring MJ, Zinda M, Clark E, Chen H
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Print publication date: 01/11/2016
Online publication date: 29/08/2016
Acceptance date: 15/08/2016
Date deposited: 30/08/2016
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
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