Aerosolized Phosphoinositide 3-Kinase γ/δ Inhibitor TG100-115 [3-[2,4-Diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease

Doukas, John; Eide, Lisa; Stebbins, Karin; Racanelli-Layton, Adrienne; Dellamary, Luis; Martin, Michael; Dneprovskaia, Elena; Noronha, Glenn; Söll, Richard; Wrasidlo, Wolfgang; Acevedo, Lisette M.; Cheresh, David A.

doi:10.1124/jpet.108.144311

Cited by 99 publications

(79 citation statements)

References 45 publications

(52 reference statements)

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“…In the acute model, the degree of inhibition achieved was comparable with that of the well characterized phosphodiesterase 4 inhibitor rolipram. Dexa- at ASPET Journals on May 9, 2018 jpet.aspetjournals.org Downloaded from methasone failed to inhibit neutrophil influx, which is consistent with previous literature reports showing that rodent smoke models are steroid-resistant (Leclerc et al, 2006;Doukas et al, 2009).…”

Section: Discussionsupporting

confidence: 81%

“…served as a negative control. This dose of dexamethasone has been shown to inhibit lipopolysaccharide-induced pulmonary neutrophilia (Medicherla et al, 2008;Doukas et al, 2009). The vehicle for rolipram was 0.5% MC, whereas that for dexamethasone was 25% 2-hydroxypropyl-␤-cyclodextrin (Sigma-Aldrich).…”

Section: Cigarette Smoke Exposurementioning

confidence: 99%

“…In acute models (Ͻ4 days) inflammation is predominantly neutrophilic (Leclerc et al, 2006;Morris et al, 2008;Doukas et al, 2009), whereas in subchronic exposure models (Ͻ30 days), the inflammatory phenotype is more complex and includes mucus hypersecretion and epithelial hyperplasia (Medicherla et al, 2008).…”

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confidence: 99%

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Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Stebbins¹,

Broadhead²,

Baccei³

et al. 2009

J Pharmacol Exp Ther

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Prostaglandin D 2 (PGD 2 ) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD 2 is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD 2 and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8ϩ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2Ј-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4Ј-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dosedependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.Chronic obstructive pulmonary disease (COPD) is a complex disease in which airflow obstruction is not fully reversible. It is a chronic, progressive inflammatory condition of the small airways and lung parenchyma that is characterized by elevated pulmonary macrophages, neutrophils, and CD8ϩ T cells. Proinflammatory mediators, including IL-8, MCP-1, and IL-1␤, are elevated in bronchoalveolar lavage fluid (BALF) and sputum samples obtained from patients with COPD (Keatings et al., 1996;Yamamoto et al., 1997;Hill et al., 1999;Soler et al., 1999). Chronic inflammation contributes to the decline in pulmonary function associated with chronic bronchitis, mucus hypersecretion, and emphysema via the release of proinflammatory mediators, reactive oxygen species, and tissue degradation enzymes (Corrigan and

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Section: Discussionsupporting

confidence: 81%

Section: Cigarette Smoke Exposurementioning

confidence: 99%

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Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Stebbins¹,

Broadhead²,

Baccei³

et al. 2009

J Pharmacol Exp Ther

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“…PI3K␥ has been implicated in the pathogenesis of asthma. For example, knockout of PI3K␥ or treatment with aerosolized TG100-115, an inhibitor of PI3Ks ␥ and ␦, markedly reduced allergen-induced asthmatic symptoms in experimental animals, including eosinophilic airway inflammation and AHR (Doukas et al, 2009;Lim et al, 2009;Takeda et al, 2009). Thus, PI3K␥ may be a novel therapeutic target in asthma and other respiratory diseases (Marwick et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

Jiang¹,

Xie²,

Abel³

et al. 2012

J Pharmacol Exp Ther

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We recently reported that phosphoinositide 3-kinase ␥ (PI3K␥) directly regulates airway smooth muscle (ASM) contraction by modulating Ca 2ϩ oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3K␥ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 g per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3K␥-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca 2ϩ transient and increased Ca 2ϩ oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3K␥ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3K␥ by 70% only reduced the initial Ca 2ϩ transient by 20 to 30% but markedly attenuated Ca 2ϩ oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3K␥ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3K␥ inhibitor can ameliorate AHR in a murine model of asthma.

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“…PI3K δ and γ isoforms are implicated in inflammatory cell recruitment and activation [129]. An inhaled dual PI3Kδ/γ inhibitor, TG100-115, reduces airway inflammation induced by allergen and cigarette smoke in murine models 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 and restores corticosteroid sensitivity in the smoke model [130]. A PI3Kδ/γ inhibitor RV1729 has undergone early stage clinical evaluation in COPD, although no results are published (ClinicalTrials.gov Identifier: NCT02140346).…”

Section: Pi3kinase Inhibitorsmentioning

confidence: 99%

Addressing corticosteroid insensitivity in adults with asthma

Thomson

2016

Expert Review of Respiratory Medicine

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Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

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Aerosolized Phosphoinositide 3-Kinase γ/δ Inhibitor TG100-115 [3-[2,4-Diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a Therapeutic Candidate for Asthma and Chronic Obstructive Pulmonary Disease

Cited by 99 publications

References 45 publications

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

Addressing corticosteroid insensitivity in adults with asthma

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