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Ref Type Journal Article
PMID (27573426)
Authors 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 GB, Fawell SE, Waring MJ, Zinda M, Clark E, Chen H
Title AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.
Journal Molecular cancer therapeutics
Vol 15
Issue 11
Date 2016 Nov
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD5153 AZD5153 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD5153 AZD-5153 BRD4 Inhibitor 7 AZD5153 is a selective BET inhibitor that binds to BRD4 bivalently, resulting in enhanced anti-tumor activity (PMID: 27573426, PMID: 31392631).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS mutant acute myeloid leukemia predicted - sensitive AZD5153 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD5153 inhibited proliferation of acute myeloid leukemia cells harboring NRAS mutation in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). 27573426
KMT2A - AFF1 acute myeloid leukemia predicted - sensitive AZD5153 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD5153 inhibited proliferation of acute myeloid leukemia cells harboring KMT2A-AFF1 (MLL-AF4) in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). 27573426
KMT2A - AFF1 acute lymphoblastic leukemia predicted - sensitive AZD5153 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD5153 inhibited proliferation of acute lymphocytic leukemia cells harboring KMT2A-AFF1 (MLL-AF4) in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). 27573426
Unknown unknown multiple myeloma not applicable AZD5153 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD5153 inhibited proliferation of multiple myeloma cell lines harboring t (11;14) translocation in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). 27573426