American Association for Cancer Research
15357163mct160141-sup-163557_1_supp_3552661_596p5d.xlsx (46.34 kB)

Supplementary Table 2 from AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies

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posted on 2023-04-03, 15:23 authored by 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, Jonathan R. Dry, Corinne Reimer, Paul Lyne, Gordon B. Mills, Stephen E. Fawell, Michael J. Waring, Michael Zinda, Edwin Clark, Huawei Chen

Differentially expressed genes with AZD5153 treatment



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. Mol Cancer Ther; 15(11); 2563–74. ©2016 AACR.