Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	11	2016 Nov	2563-2574	Mol Cancer Ther

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	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD5153		AZD-5153	BRD4 Inhibitor 10	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