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

Rhyasen, Garrett W.; Hattersley, Maureen M.; Yao, Yi; Dulak, Austin; Wang, Wenxian; Petteruti, Philip; Dale, Ian L.; Boiko, Scott; Cheung, Tony; Zhang, Jingwen; Wen, Shenghua; Castriotta, Lillian; Lawson, Deborah; Collins, Michael; Bao, Larry; Ahdesmäki, Miika J.; Walker, Graeme E.; O’Connor, Greg; Yeh, Tammie C.; Rabow, Alfred A.; Dry, Jonathan R.; Reimer, Corinne; Lyne, Paul; Mills, Gordon B.; Fawell, Stephen E.; Waring, Michael J.; Zinda, Michael; Clark, Edwin; Chen, Huawei

doi:10.1158/1535-7163.mct-16-0141

Cited by 128 publications

(136 citation statements)

References 34 publications

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“…Such inhibition could be achieved via a single compound, which targets both BDs or through the combined use of two compounds, supplied independently or covalently linked as a bivalent BD inhibitor. Indeed, dual-warhead BET inhibitors that simultaneously engage both BDs within a single BET protein have recently been described, which possess greatly enhanced biochemical and cellular potency as well as increased efficacy in animal disease models relative to monovalent inhibitors474849. Alternatively, one could envisage a Proteolysis Targeting Chimera approach, whereby a single BD inhibitor conjugated to a ligand for an E3 ubiquitin ligase would trigger the degradation of Ca Bdf1, as recently demonstrated for human BET proteins50515253.…”

Section: Discussionmentioning

confidence: 99%

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

et al. 2017

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Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

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Section: Discussionmentioning

confidence: 99%

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

et al. 2017

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“…Compound 103 is a bivalent and potent BRD4 inhibitor with IC 50 values of 5 nM against full length BRD4 and 1.6 μ M against BRD4 BD1. 171 In a xenograft model of MV4-11, a dose-dependent TGI was observed for 1 (TGI = 72%), 2.5, and 5 mg/kg (regression) daily oral doses of compound 103 .…”

Section: Discovery and Development Of Brd4 Inhibitorsmentioning

confidence: 95%

Drug Discovery Targeting Bromodomain-Containing Protein 4

et al. 2017

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BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.

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“…Recent studies have proposed BRD4 as an important oncotarget protein for prostate cancer [12][13][14]. Here, we show that AZD5153, a novel bivalent BRD4 inhibitor [21][22][23], inhibited survival and proliferation of established (PC-3 and LNCaP lines) and primary human prostate cancer cells. Further, AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 68%

AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

Shen¹,

Chen²,

Zhou³

et al. 2018

Cell Physiol Biochem

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Backgrounds/Aims: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. Methods: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H³] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153’s activity in vivo. Results: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. Conclusion: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.

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

Cited by 128 publications

References 34 publications

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Drug Discovery Targeting Bromodomain-Containing Protein 4

AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo

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