Validation of the epigenetic reader bromodomain-containing protein 4 (BRD4) as a therapeutic target for treatment of airway remodeling

Dougherty, 2009, Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype, Clin. Exp. Allergy, 39, 193, 10.1111/j.1365-2222.2008.03157.x Takizawa, 2008, Remodeling in small airways of asthma, Respir. Med. CME, 1, 69, 10.1016/j.rmedc.2008.05.001 Cook, 2014, Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework, Nat. Rev. Drug Discov., 13, 419, 10.1038/nrd4309 Lambrecht, 2012, The airway epithelium in asthma, Nat. Med., 18, 684, 10.1038/nm.2737 Tian, 2019, Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling, J. Allergy Clin. Immunol., 143, 1380, 10.1016/j.jaci.2018.09.029 Denney, 2015, Pulmonary epithelial cell-derived cytokine TGF-beta1 is a critical cofactor for enhanced innate lymphoid cell function, Immunity, 43, 945, 10.1016/j.immuni.2015.10.012 Zhao, 2017, Systematic analysis of cell-type differences in the epithelial secretome reveals insights into the pathogenesis of respiratory syncytial virus-induced lower respiratory tract infections, J. Immunol., 198, 3345, 10.4049/jimmunol.1601291 Tian, 2018, Selective antagonists of the bronchiolar epithelial NF-kappaB-bromodomain-containing protein 4 pathway in viral-induced airway inflammation, Cell Rep., 23, 1138, 10.1016/j.celrep.2018.03.106 Tian, 2018, Central role of the NF-kappaB pathway in the Scgb1a1-expressing epithelium in mediating respiratory syncytial virus-induced airway inflammation, J. Virol., 92, 10.1128/JVI.00441-18 Devaiah, 2012, BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain, Proc. Natl. Acad. Sci. U. S. A., 109, 6927, 10.1073/pnas.1120422109 Brasier, 2011, RelA Ser276 phosphorylation-coupled Lys310 acetylation controls transcriptional elongation of inflammatory cytokines in respiratory syncytial virus infection, J. Virol., 85, 11752, 10.1128/JVI.05360-11 Yang, 2015, Systematic determination of human cyclin dependent kinase (CDK)-9 interactome identifies novel functions in RNA splicing mediated by the DEAD box (DDX)-5/17 RNA helicases, Mol. Cell Proteomic., 14, 2701, 10.1074/mcp.M115.049221 Liu, 2017, Drug discovery targeting bromodomain-containing protein 4, J. Med. Chem., 60, 4533, 10.1021/acs.jmedchem.6b01761 Liu, 2018, Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation, Eur. J. Med. Chem., 151, 450, 10.1016/j.ejmech.2018.04.006 Tian, 2017, BRD4 couples NF-kappaB/RelA with airway inflammation and the IRF-RIG-I amplification loop in respiratory syncytial virus infection, J. Virol., 91, 10.1128/JVI.00007-17 Kalluri, 2009, The basics of epithelial-mesenchymal transition, J. Clin. Invest., 119, 1420, 10.1172/JCI39104 Tian, 2015, Analysis of the TGFbeta-induced program in primary airway epithelial cells shows essential role of NF-kappaB/RelA signaling network in type II epithelial mesenchymal transition, BMC Genomics, 16, 529, 10.1186/s12864-015-1707-x Chang, 2016, Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition, Nucleic Acids Res., 44, 2514, 10.1093/nar/gkw126 Ijaz, 2014, Systems biology approaches to understanding epithelial mesenchymal transition (EMT) in mucosal remodeling and signaling in asthma, World Allergy Organ J, 7, 13, 10.1186/1939-4551-7-13 Jordan, 2011, Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer, Cell Cycle, 10, 2865, 10.4161/cc.10.17.17188 Katsuno, 2013, TGF-beta signaling and epithelial-mesenchymal transition in cancer progression, Curr. Opin. Oncol., 25, 76, 10.1097/CCO.0b013e32835b6371 Yang, 2003, Hierarchical model of gene regulation by transforming growth factor beta, Proc. Natl. Acad. Sci. U. S. A., 100, 10269, 10.1073/pnas.1834070100 Mullen, 2011, Master transcription factors determine cell-type-specific responses to TGF-beta signaling, Cell, 147, 565, 10.1016/j.cell.2011.08.050 Lamouille, 2014, Molecular mechanisms of epithelial-mesenchymal transition, Nat. Rev. Mol. Cell Biol., 15, 178, 10.1038/nrm3758 Bracken, 2008, A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition, Cancer Res., 68, 7846, 10.1158/0008-5472.CAN-08-1942 Lu, 2013, MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination, Proc. Natl. Acad. Sci. U. S. A., 110, 18144, 10.1073/pnas.1318192110 Hoot, 2010, HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion, J. Clin. Invest., 120, 3606, 10.1172/JCI43304 Tian, 2016, BRD4 mediates NF-kappaB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation, Am. J. Physiol. Lung Cell Mol. Physiol., 311, L1183, 10.1152/ajplung.00224.2016 Wang, 2012, Bromodomain protein Brd4 associated with acetylated chromatin is important for maintenance of higher-order chromatin structure, J. Biol. Chem., 287, 10738, 10.1074/jbc.M111.323493 Whyte, 2013, Master transcription factors and mediator establish super-enhancers at key cell identity genes, Cell, 153, 307, 10.1016/j.cell.2013.03.035 Huang, 2009, Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA, Mol. Cell Biol., 29, 1375, 10.1128/MCB.01365-08 Tian, 2013, CDK9-dependent transcriptional elongation in the innate interferon-stimulated gene response to respiratory syncytial virus infection in airway epithelial cells, J. Virol., 87, 7075, 10.1128/JVI.03399-12 Devaiah, 2016, BRD4 is a histone acetyltransferase that evicts nucleosomes from chromatin, Nat. Struct. Mol. Biol., 23, 540, 10.1038/nsmb.3228 Zhang, 2017, Quantitative assessment of the effects of trypsin digestion methods on affinity purification-mass spectrometry-based protein–protein interaction analysis, J. Proteome Res., 16, 3068, 10.1021/acs.jproteome.7b00432 Ijaz, 2017, Coordinate activities of BRD4 and CDK9 in the transcriptional elongation complex are required for TGFb-induced Nox4 expression and myofibroblast transdifferentiation, Cell Death Differ, 8, e2606, 10.1038/cddis.2016.434 Carroll, 2000, The airway longitudinal elastic fiber network and mucosal folding in patients with asthma, Am. J. Respir. Crit. Care Med., 161, 244, 10.1164/ajrccm.161.1.9805005 Karvonen, 2013, Myofibroblast expression in airways and alveoli is affected by smoking and COPD, Respir. Res., 14, 84, 10.1186/1465-9921-14-84 Kim, 2006, Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix, Proc. Natl. Acad. Sci. U. S. A., 103, 13180, 10.1073/pnas.0605669103 Evans, 1999, The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit, Am. J. Respir. Cell Mol. Biol., 21, 655, 10.1165/ajrcmb.21.6.3807 Duan, 2018, Targeting Brd4 for cancer therapy: inhibitors and degraders, MedChemComm, 9, 1779, 10.1039/C8MD00198G Yang, 2019, Small-molecule PROTAC degraders of the bromodomain and extra terminal (BET) proteins – a review, Drug Discov. Today Technol., 31, 43, 10.1016/j.ddtec.2019.04.001 Kharenko, 2017, Novel approaches to targeting BRD4, Drug Discov. Today Technol., 24, 19, 10.1016/j.ddtec.2017.10.003 Cochran, 2019, Bromodomains: a new target class for drug development, Nat. Rev. Drug Discov., 18, 609, 10.1038/s41573-019-0030-7 Dhalluin, 1999, Structure and ligand of a histone acetyltransferase bromodomain, Nature, 399, 491, 10.1038/20974 Sun, 2018, BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency, Cancer Cell, 33, 401, 10.1016/j.ccell.2018.01.019 Belkina, 2012, BET domain co-regulators in obesity, inflammation and cancer, Nat. Rev. Cancer, 12, 465, 10.1038/nrc3256 Bao, 2017, Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IkappaBalpha, Proc. Natl. Acad. Sci. U. S. A., 114, E3993, 10.1073/pnas.1700109114 Zhu, 2012, Reactivation of latent HIV-1 by inhibition of BRD4, Cell Rep., 2, 807, 10.1016/j.celrep.2012.09.008 Niu, 2019, Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV, J. Clin. Invest., 129, 3361, 10.1172/JCI120633 Duan, 2017, BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure, Sci. Transl. Med., 9, eaah5084, 10.1126/scitranslmed.aah5084 Korb, 2015, BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice, Nat. Neurosci., 18, 1464, 10.1038/nn.4095 Zhou, 2018 Li, 2013, The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation, Nucleic Acids Res., 41, 277, 10.1093/nar/gks976 Brewster, 1990, Myofibroblasts and subepithelial fibrosis in bronchial asthma, Am. J. Respir. Cell Mol. Biol., 3, 507, 10.1165/ajrcmb/3.5.507 Zou, 2014, Brd4 maintains constitutively active NF-kappaB in cancer cells by binding to acetylated RelA, Oncogene, 33, 2395, 10.1038/onc.2013.179 Tian, 2019, Efficacy of novel highly specific bromodomain-containing protein 4 inhibitors in innate inflammation-driven airway remodeling, Am. J. Respir. Cell Mol. Biol., 60, 68, 10.1165/rcmb.2017-0445OC Zhao, 2019, Pharmacoproteomics reveal novel protective activity of bromodomain containing 4 inhibitors on vascular homeostasis in TLR3-mediated airway remodeling, J. Proteomics, 205, 103415, 10.1016/j.jprot.2019.103415 Nair, 2010, Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis, Lancet, 375, 1545, 10.1016/S0140-6736(10)60206-1 Tang, 2013, Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis, Am. J. Pathol., 183, 470, 10.1016/j.ajpath.2013.04.020