AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.

Autor:	Rhyasen GW; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Hattersley MM; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Yao Y; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Dulak A; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Wang W; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Petteruti P; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Dale IL; AstraZeneca, Macclesfield, Cheshire, UK., Boiko S; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Cheung T; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Zhang J; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Wen S; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Castriotta L; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Lawson D; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Collins M; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Bao L; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Ahdesmaki MJ; AstraZeneca, Macclesfield, Cheshire, UK., Walker G; AstraZeneca, Macclesfield, Cheshire, UK., O'Connor G; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Yeh TC; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Rabow AA; AstraZeneca, Macclesfield, Cheshire, UK., Dry JR; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Reimer C; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Lyne P; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Mills GB; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Fawell SE; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Waring MJ; AstraZeneca, Macclesfield, Cheshire, UK., Zinda M; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Clark E; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts., Chen H; Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts. raymond.chen@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Nov; Vol. 15 (11), pp. 2563-2574. Date of Electronic Publication: 2016 Aug 29.
DOI:	10.1158/1535-7163.MCT-16-0141
Abstrakt:	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. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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