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. Mol Cancer Ther; 15(11); 2563-74. ©2016 AACR.
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Garrett W
authors: GW
authors: Rhyasen
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Maureen M
authors: MM
authors: Hattersley
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Yi
authors: Y
authors: Yao
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Austin
authors: A
authors: Dulak
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Wenxian
authors: W
authors: Wang
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Philip
authors: P
authors: Petteruti
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Ian L
authors: IL
authors: Dale
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Scott
authors: S
authors: Boiko
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Tony
authors: T
authors: Cheung
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Jingwen
authors: J
authors: Zhang
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Shenghua
authors: S
authors: Wen
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Lillian
authors: L
authors: Castriotta
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Deborah
authors: D
authors: Lawson
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Michael
authors: M
authors: Collins
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Larry
authors: L
authors: Bao
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Miika J
authors: MJ
authors: Ahdesmaki
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Graeme
authors: G
authors: Walker
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Greg
authors: G
authors: O'Connor
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Tammie C
authors: TC
authors: Yeh
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Alfred A
authors: AA
authors: Rabow
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Jonathan R
authors: JR
authors: Dry
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Corinne
authors: C
authors: Reimer
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Paul
authors: P
authors: Lyne
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gordon B
authors: GB
authors: Mills
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Stephen E
authors: SE
authors: Fawell
authors: AstraZeneca, Macclesfield, Cheshire, UK.
authors: Michael J
authors: MJ
authors: Waring
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Michael
authors: M
authors: Zinda
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors: Edwin
authors: E
authors: Clark
authors: Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts. raymond.chen@astrazeneca.com.
authors: Huawei
authors: H
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D018797:Cell Cycle Proteins; D050684:E2F Transcription Factors; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins