Quadragenics
Epithelial injury and repair triggers compensatory changes in the airway mucosa that involves reprogramming the mucosa to produce pro-fibrotic genes important in altering the properties of the normally elastic airways. Excessive production of collagen and fibronectin results in stiffening of the airways reducing pulmonary function. A critical
signaling pathway resulting in activation of the remodeling program is mediated by bromodomain containing protein 4 (BRD4). BRD4.
signaling pathway resulting in activation of the remodeling program is mediated by bromodomain containing protein 4 (BRD4). BRD4.
Using Quadragenics small molecule inhibitiors, BRD4 Inhibition prevents airway remodeling and abnormal lung function produced by chronic exposure to aeroallergens and respiratory viruses.
BRD4 inhibitors have therapeutic application in reducing airway remodeling in patients with asthma suffering from recurrent exacerbations, most closely linked to airway remodeling and reductions in pulmonary function.
Therapeutic Indications for BRD4 inhibitors
Anti-inflammatory
BRD4 is a major mediator of airway inflammation.
Quadragenics small molecule inhibitors have been shown to block acute inflammation induced by RNA viruses and cat dander.
Inhibit remodeling
Repetitive exacerbations of asthma are linked to structural remodeling in the airway.
BRD4 mediates the mucosal injury/repair response to viral - and aeroallergen induced airway inflammation.
Quadragenics small molecule inhibitors have been restore mucosal state and reduce myofibroblast expansion
Publications
B. Tian, K. Hosoki, Z. Liu, J. Yang, Y. Zhao, H. Sun, J. Zhou, E. Rytting, L. Kaphalia, W. J. Calhoun, S. Sur and AR Brasier. Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. The Journal of allergy and clinical immunology, 6749(18)31438-6. (2019).
B. Tian, I. Patrikeev, L. Ochoa, G. Vargas, K. K. Belanger, J. Litvinov, I. Boldogh, B. T. Ameredes, M. Motamedi and AR Brasier. NF-kappaB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol 56, 506-520 (2017).
8. Z. Liu, B. Tian, H. Chen, P. Wang, AR Brasier and J. Zhou. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. European journal of medicinal chemistry 151, 450-461 (2018).
B. Tian, Z. Liu, J. Yang, H. Sun, Y. Zhao, M. Wakamiya, H. Chen, E. Rytting, J. Zhou and AR Brasier. Selective Antagonists of the Bronchiolar Epithelial NF-kappaB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23, 1138-1151 (2018).
B. Tian, Z. Liu, J. Litvinov, R. Maroto, M. Jamaluddin, E. Rytting, I. Patrikeev, L. Ochoa, G. Vargas, M. Motamedi, BT Ameredes, J. Zhou and AR Brasier. Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling. Am J Respir Cell Mol Biol. 2019 60(1):68-83.
B. Tian, K. Hosoki, Z. Liu, J. Yang, Y. Zhao, H. Sun, J. Zhou, E. Rytting, L. Kaphalia, W. J. Calhoun, S. Sur and AR Brasier. Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling. The Journal of allergy and clinical immunology, 6749(18)31438-6. (2019).
B. Tian, I. Patrikeev, L. Ochoa, G. Vargas, K. K. Belanger, J. Litvinov, I. Boldogh, B. T. Ameredes, M. Motamedi and AR Brasier. NF-kappaB Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol 56, 506-520 (2017).
8. Z. Liu, B. Tian, H. Chen, P. Wang, AR Brasier and J. Zhou. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. European journal of medicinal chemistry 151, 450-461 (2018).
B. Tian, Z. Liu, J. Yang, H. Sun, Y. Zhao, M. Wakamiya, H. Chen, E. Rytting, J. Zhou and AR Brasier. Selective Antagonists of the Bronchiolar Epithelial NF-kappaB-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23, 1138-1151 (2018).
B. Tian, Z. Liu, J. Litvinov, R. Maroto, M. Jamaluddin, E. Rytting, I. Patrikeev, L. Ochoa, G. Vargas, M. Motamedi, BT Ameredes, J. Zhou and AR Brasier. Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling. Am J Respir Cell Mol Biol. 2019 60(1):68-83.
