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ZL0454 Sale

目录号 : GC65204

ZL0454是有效,选择性的含有溴结构域的蛋白质4 (BRD4)抑制剂,对BD1和BD2的IC50分别为49和32 nM 。

ZL0454 Chemical Structure

Cas No.:2229042-77-5

规格 价格 库存 购买数量
5mg
¥2,880.00
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10mg
¥4,590.00
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25mg
¥9,450.00
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50mg
¥15,120.00
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100mg
¥23,850.00
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产品描述

ZL0454 is a potent and selective Bromodomain-containing protein 4 (BRD4) inhibitor with an IC50 of 49 and 32 nM for BD1 and BD2.

[1]. Liu Z, et al. Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur J Med Chem. 2018 May 10;151:450-461.

Chemical Properties

Cas No. 2229042-77-5 SDF Download SDF
分子式 C18H22N4O3S 分子量 374.46
溶解度 DMSO : 50 mg/mL (133.53 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.6705 mL 13.3526 mL 26.7051 mL
5 mM 0.5341 mL 2.6705 mL 5.341 mL
10 mM 0.2671 mL 1.3353 mL 2.6705 mL
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Research Update

Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

J Allergy Clin Immunol 2019 Apr;143(4):1380-1394.e9.PMID:30321559DOI:10.1016/j.jaci.2018.09.029.

Background: Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease in pulmonary function, producing morbidity. Cat dander is an aeroallergen associated with asthma risk. Objective: We sought to elucidate the mechanism of cat dander-induced inflammation-remodeling. Methods: We identified remodeling in mucosal samples from allergic asthma by using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)-BRD4 interaction was measured by using a proximity ligation assay in situ. Results: Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase-NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB-RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander. Conclusions: NF-κB-inducible BRD4 activity mediates cat dander-induced inflammation and remodeling. Therapeutic modulation of the NF-κB-BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.

Efficacy of Novel Highly Specific Bromodomain-Containing Protein 4 Inhibitors in Innate Inflammation-Driven Airway Remodeling

Am J Respir Cell Mol Biol 2019 Jan;60(1):68-83.PMID:30153047DOI:10.1165/rcmb.2017-0445OC.

NF-κB/RelA triggers innate inflammation by binding to bromodomain-containing protein 4 (BRD4), an atypical histone acetyltransferase (HAT). Although RelA·BRD4 HAT mediates acute neutrophilic inflammation, its role in chronic and functional airway remodeling is not known. We observed that BRD4 is required for Toll-like receptor 3 (TLR3)-mediated mesenchymal transition, a cell-state change that is characteristic of remodeling. We therefore tested two novel highly selective BRD4 inhibitors, ZL0420 and ZL0454, for their effects on chronic airway remodeling produced by repetitive TLR3 agonist challenges, and compared their efficacy with that of two nonselective bromodomain and extraterminal (BET) protein inhibitors, JQ1 and RVX208. We observed that ZL0420 and ZL0454 more potently reduced polyinosinic:polycytidylic acid-induced weight loss and fibrosis as assessed by microcomputed tomography and second harmonic generation microscopy. These measures correlated with the collagen deposition observed in histopathology. Importantly, the ZL inhibitors were more effective than the nonselective BET inhibitors at equivalent doses. The ZL inhibitors had significant effects on lung physiology, reversing TLR3-associated airway hyperresponsiveness and increasing lung compliance in vivo. At the molecular level, ZL inhibitors reduced elaboration of the transforming growth factor-β-induced growth program, thereby preventing mucosal mesenchymal transition and disrupting BRD4 HAT activity and complex formation with RelA. We also observed that ZL0454 treatment blocked polyinosinic:polycytidylic acid-associated expansion of the α-SMA1+/COL1A+ myofibroblast population and prevented myofibroblast transition in a coculture system. We conclude that 1) BRD4 is a central effector of the mesenchymal transition that results in paracrine activation of myofibroblasts, mechanistically linking innate inflammation to airway hyperresponsiveness and fibrosis, and 2) highly selective BRD4 inhibitors may be effective in reversing the effects of repetitive airway viral infections on innate inflammation-mediated remodeling.

Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation

Eur J Med Chem 2018 May 10;151:450-461.PMID:29649741DOI:10.1016/j.ejmech.2018.04.006.

A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2O molecule. Both compounds 28 and 35 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, ISG56, IL-8, and Groβ genes in cultured human small airway epithelial cells (hSAECs). More importantly, they also demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral-induced airway inflammation.

Pharmacoproteomics reveal novel protective activity of bromodomain containing 4 inhibitors on vascular homeostasis in TLR3-mediated airway remodeling

J Proteomics 2019 Aug 15;205:103415.PMID:31195152DOI:10.1016/j.jprot.2019.103415.

Small molecule inhibitors of the epigenetic regulator bromodomain-containing protein 4 (BRD4) are potential therapeutics for viral and allergen-induced airway remodeling. A limitation of their preclinical advancement is the lack of detailed understanding of mechanisms of action and biomarkers of effect. We report a systems-level pharmacoproteomics in a standardized murine model of toll-like receptor TLR3-NFκB/RelA innate inflammation in the absence or presence of a highly selective BRD4 inhibitor (ZL0454) or nonselective bromodomain and extraterminal domain inhibitor (JQ1). Proteomics of bronchoalveolar lavage fluid (BALF) secretome and exosomal proteins from this murine model revealed increased, selective, capillary leak associated with pericyte-myofibroblast transition, a phenomenon blocked by BRD4 inhibitors. BALF proteomics also suggested that ZL0454 better reduced the vascular leakage and extracellular matrix deposition than JQ1. A significant subset of inflammation-mediated remodeling factors was also identified in a mouse model of idiopathic pulmonary fibrosis produced by bleomycin. BALF exosome analysis indicated that BRD4 inhibitors reduced the induction of exosomes enriched in coagulation factors whose presence correlated with interstitial fibrin deposition. Finally, BALF samples from humans with severe asthma demonstrated similar upregulations of ORM2, APCS, SPARCL1, FGA, and FN1, suggesting their potential as biomarkers for early detection of airway remodeling and/or monitoring of therapy response. SIGNIFICANCE: Repetitive and chronic viral upper respiratory tract infections trigger toll-like receptor (TLR)3-NFκB/RelA mediated airway remodeling which is linked to a progressive decline in pulmonary function in patients with asthma and chronic obstructive pulmonary disease. Small molecule inhibitors of the epigenetic regulator bromodomain-containing protein 4 (BRD4) are potential therapeutics for viral and allergen-induced airway remodeling. A limitation of their preclinical advancement is the lack of detailed understanding of mechanisms of action and biomarkers of effect. Our study revealed that the activation of (TLR)3-NFκB/RelA pathway in the lung induced an elevation in coagulation, complement, and platelet factors, indicating the increased vascular leak during airway remodeling. The mechanism of vascular leakage was chronic inflammation-induced pericyte-myofibroblast transition, which was blocked by BRD4 inhibitors. Finally, proteomics analysis of the bronchoalveolar lavage fluid samples from humans with severe asthma demonstrated similar findings that we observed in the animal model.

Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Front Mol Biosci 2021 Oct 26;8:728661.PMID:34765643DOI:10.3389/fmolb.2021.728661.

Bromodomain-containing protein 4 plays a central role in coordinating the complex epigenetic component of the innate immune response. Previous studies implicated BRD4 as a component of a chromatin-modifying complex that is dynamically recruited to a network of protective cytokines by binding activated transcription factors, polymerases, and histones to trigger their rapid expression via transcriptional elongation. Our previous study extended our understanding of the airway epithelial BRD4 interactome by identifying over 100 functionally important coactivators and transcription factors, whose association is induced by respiratory syncytial virus (RSV) infection. RSV is an etiological agent of recurrent respiratory tract infections associated with exacerbations of chronic obstructive pulmonary disease. Using a highly selective small-molecule BRD4 inhibitor (ZL0454) developed by us, we extend these findings to identify the gene regulatory network dependent on BRD4 bromodomain (BD) interactions. Human small airway epithelial cells were infected in the absence or presence of ZL0454, and gene expression profiling was performed. A highly reproducible dataset was obtained which indicated that BRD4 mediates both activation and repression of RSV-inducible gene regulatory networks controlling cytokine expression, interferon (IFN) production, and extracellular matrix remodeling. Index genes of functionally significant clusters were validated independently. We discover that BRD4 regulates the expression of its own gene during the innate immune response. Interestingly, BRD4 activates the expression of NFκB/RelA, a coactivator that binds to BRD4 in a BD-dependent manner. We extend this finding to show that BRD4 also regulates other components of its functional interactome, including the Mediator (Med) coactivator complex and the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) subunits. To provide further insight into mechanisms for BRD4 in RSV expression, we mapped 7,845 RSV-inducible Tn5 transposase peaks onto the BRD4-dependent gene bodies. These were located in promoters and introns of cytostructural and extracellular matrix (ECM) formation genes. These data indicate that BRD4 mediates the dynamic response of airway epithelial cells to RNA infection by modulating the expression of its coactivators, controlling the expression of host defense mechanisms and remodeling genes through changes in promoter accessibility.