<scp>PI3K</scp> signalling in chronic obstructive pulmonary disease and opportunities for therapy

Moradi, Sharif; Jarrahi, Esmaeil; Ahmadi, Ali; Salimian, Jafar; Karimi, Mehrdad; Zarei, Azadeh; Jamalkandi, Sadegh Azimzadeh; Ghanei, Mostafa

doi:10.1002/path.5696

Cited by 20 publications

(12 citation statements)

References 163 publications

(193 reference statements)

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“…In contrast, the variation of 3-fluoro-4-methoxyphenyl to 3-fluoro-4-isopropox-yphenyl (20) and 3-fluoro-4-ethoxyphenyl (22) would lead to significantly lower PI3Kδ inhibitory activity, indicating that the methoxy group was essential in the interaction with PI3Kδ. Besides, when this aryl group was further changed to 3,4dimethoxyphenyl (23) and other heterocyclic rings such as pyridine-2-methoxy-5-yl (24), pyrimidine-2-methoxy-5-yl (25), and 1-methylpyrazole-4-yl (26), these compounds would also possess high PI3Kδ inhibitory activity (IC 50 ranges from 2.6 to 4.3 nM). On the other hand, when the R 1 group of 21 was changed to ethyl for delivering compound 27, and the inhibitory activity slightly decreased (IC 50 = 17.3 ± 1.6 nM).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…For example, compounds 29, 30, and 31 showed good inhibitory activities against PI3Kδ and also exhibited remarkable anti-inflammatory activities. At this stage, those compounds with slight toxicity (cell viability below 80% at 10 μM) were excluded for further tests (Figure S1), 13 including compounds 23,26,33,34,38,39, and 42−46. Next, we took together the PI3Kδ potency, anti-inflammatory activity, and toxicity, and selected compounds 29, 30, 31, and 36 as promising candidates for further multidose evaluation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…1 H NMR (500 MHz, CDCl 3 ) δ 8.81 (s, 2H), 8.50 (s, 1H), 8.32 (t, J = 2.0 Hz, 1H), 8.06−7.99 (m, 1H), 7.97−7.88 (m, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.71−7.64 (m, 2H), 7.19−7.09 (m, 1H), 6.73 (q, J = 7.0 Hz, 1H), 5.55 (brs, 2H), 4.08 (s, 3H), 3.15 (s, 3H), 2.23 (d, J = 7.0 Hz, 3H). 13 (26). Yield 68%.…”

Section: (S)-1-(1-(6-chloro-1-(pyridin-3-yl)-1h-indazol-3-yl)ethyl)-3...mentioning

confidence: 99%

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Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Tang,

Zheng,

Bao

et al. 2023

J. Med. Chem.

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PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. ( S )-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of ( S )-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, ( S )-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: (S)-1-(1-(6-chloro-1-(pyridin-3-yl)-1h-indazol-3-yl)ethyl)-3...mentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Tang,

Zheng,

Bao

et al. 2023

J. Med. Chem.

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“…The PI3K signaling pathway is extremely important for mediating various forms of cellular responses, ranging from cell survival, growth, proliferation, and differentiation to DNA repair and apoptosis in different developmental and tissue contexts. The expression of PI3K and its downstream mediators are upregulated during lung and airway remodeling in COPD [ 44 ]. The differential expression of PI3K during COPD progression implies dynamic regulation under pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Tiao‐Bu‐Fei‐Shen Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K‐Akt Signaling Pathway and Promoting GRα Expression

Zhou

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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Objective. To predict and determine the mechanism through which Tiao-Bu-Fei-Shen (TBFS) formula improves glucocorticoid resistance in chronic obstructive pulmonary disease (COPD), using network pharmacology, molecular docking technology, and in vitro studies. Methods. The main active components and associated targets of TBFS were screened using the systems pharmacology database of traditional Chinese medicine database (TCMSP). The main COPD targets were retrieved from the Human Gene (GeneCards) and DrugBank databases. A protein-protein interaction (PPI) network was constructed using the protein interaction platform STRING and Cytoscape 3.6.1. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genome Pathway (KEGG) analyses were performed using the biological information annotation database Metascape. Molecular docking was performed using the AutoDock Vina software. THP-1 monocytes were treated with TBFS-containing serum and cigarette smoke extract (CSE) for 48 h, and cell proliferation in each group was determined using cell counting kit-8 (CCK-8). A COPD cell model was constructed by stimulating THP-1 monocytes with CSE for 12 h. A lentivirus vector for RNA interference of histone deacetylase 2 (HDAC2) gene was constructed and transfected into the THP-1 monocytes, and the transfection efficiency was verified using quantitative polymerase chain reaction (qPCR) and western blotting (WB). The expression of HDAC2 in each group of cells was detected using qPCR, and the expression of HDAC2, phosphoinositide-3 kinase (PI3K) p85α, glucocorticoid receptor α (GRα), and P-AKT1 in each group of cells was detected through WB. Results. A total of 344 TBFS active components, 249 related drug targets, 1,171 COPD target proteins, and 138 drug and disease intersection targets were obtained. Visual analysis of the PPI network map revealed that the core COPD targets of TBFS were AKT1, IL-6, TNF, TP53, and IL1-β. KEGG pathway enrichment analysis resulted in the identification of 20 signaling pathways as the main pathways involved in the action of TBFS against COPD, including the PI3K-Akt, TNF, and IL-17 signaling pathways. Molecular docking experiments revealed a strong binding capacity of kaempferol, luteolin, and quercetin to the ATK1 protein in TBFS, with quercetin performing the best. PCR results showed that treatment with TBFS significantly increased the expression levels of HDAC2 in the COPD model. WB results showed that TBFS treatment significantly increased the expression levels of GRα and HDAC2 in the COPD model, while reducing the expression levels of P-AKT1. Conclusion. TBFS treatment improves glucocorticoid resistance observed in COPD through downregulation of the PI3K-Akt signaling pathway and promotion of GRα expression.

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“… 21 , 22 Besides, increased expression of phosphoinositide-3-kinase (PI3K) and its downstream mediators (eg, protein kinase B (AKT/PKB), phosphatase and tensin homolog (PTEN), mammalian target of rapamycin (mTOR)), contributing to a vicious cycle of inflammation, innate and adaptive immunity, oxidative stress, and epithelial-mesenchymal transition (EMT), have been reported in COPD. 23 …”

Section: Cellular and Molecular Perspectives Of Disease Mechanism In ...mentioning

confidence: 99%

Conventional, Complementary and Alternative Medicines: Mechanistic Insights into Therapeutic Landscape of Chronic Obstructive Pulmonary Disease

Arezina¹,

Chen²,

Wang³

2023

COPD

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COPD (chronic obstructive pulmonary disease) is a major public health concern associated with significant morbidity and mortality worldwide. Current therapeutic guidelines for this disease recommend starting with an inhaled bronchodilator, stepping up to combination therapy as necessary, and/or adding inhaled corticosteroids as symptoms and airflow obstruction progress. However, no drug therapy exists to stop disease progression. The mechanistic definition underlying COPD pathogenesis remains poorly understood, it is generally accepted that oxidative stress and the altered immune response of low-grade airway inflammation are major factors contributing to COPD development. There are several potential therapeutic targets that are currently under investigation, including immune regulatory pathways in inflammation and lung-associated steroid resistance induced by oxidative stress signaling cascades. Patients with COPD have increased levels of inflammatory mediators, including lipid and peptide mediators, as well as a network of cytokines and chemokines that maintain inflammatory immune response and recruit circulating cells into the lungs. Many of these proinflammatory mediators are regulated by nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs), such as p38 MAPK. Increased oxidative stress is a key driving mechanism in perpetuating inflammation and lung injury. Furthermore, many proteases that degrade elastin fibres are secreted by airway resident infiltrating immune cells in COPD patients. In this perspective, we discuss novel aspects of signaling pathway activation in the context of inflammation and oxidative stress, and the broad view of potential effective pharmacotherapies that target the underlying mechanistic disease process in COPD.

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PI3K signalling in chronic obstructive pulmonary disease and opportunities for therapy

Cited by 20 publications

References 163 publications

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Tiao‐Bu‐Fei‐Shen Formula Improves Glucocorticoid Resistance of Chronic Obstructive Pulmonary Disease via Downregulating the PI3K‐Akt Signaling Pathway and Promoting GRα Expression

Conventional, Complementary and Alternative Medicines: Mechanistic Insights into Therapeutic Landscape of Chronic Obstructive Pulmonary Disease

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