Investigation into the anti-airway inflammatory role of the PI3Kγ inhibitor JN-PK1: An in vitro and in vivo study

Xiong, Wendian; Jia, Lei; Liang, Jianying; Cai, Yanfei; Chen, Yun; Nie, Yunjuan; Jin, Jian; Zhu, Jingyu

doi:10.1016/j.intimp.2022.109102

Cited by 8 publications

(4 citation statements)

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“…Class IA PI3Ks are triggered by a cascade of receptor tyrosine kinases (RTK), while class IB PI3K is activated by G protein-coupled receptors (GPCR) such as C5a, initiating downstream signaling pathways [6]. In contrast to the wide distribution of PI3Kα and β, PI3Kγ and PI3Kδ are predominantly expressed in the immune system, specifically the leukocytes [7,8]. Their selective expression of γ and δ closely ties them to human immune function, with the two subtypes fulfilling non-redundant roles [9].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, some PI3Kγ inhibitors have been reported to be useful for the treatment of asthma [19][20][21][22][23]. Therefore, PI3Kγ is anticipated to serve as a potential therapeutic target for asthma.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, JN-KI3 reduced LPS-activated Akt phosphorylation and downregulated the transcription and expression of TNF-α, IL-6, and IL-1β in a dose-dependent manner, suggesting that JN-KI3 can diminish the production of inflammatory factors by modulating the PI3K/Akt pathway. These in vitro results suggest that JN-KI3 may yield anti-inflammatory effects by specifically inhibiting the PI3Kγ signaling pathway.Functional studies have substantiated the significant role of PI3Kγ in regulating inflammation, particularly in lung diseases[19]. Therefore, to examine the hypothesis that JN-KI3 can function as an inhibitor for pulmonary inflammation, we constructed a mouse asthma model induced by OVA.…”

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confidence: 99%

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Evaluating the anti-inflammatory potential of JN-KI3: the therapeutic role of PI3Kγ- selective inhibitors in asthma treatment

Jia,

Ma,

Xiong

et al. 2024

Preprint

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Introduction Asthma is a chronic airway inflammatory disease of the airways characterized by the involvement of numerous inflammatory cells and factors. Therefore, targeting airway inflammation is one of the crucial strategies for developing novel drugs in the treatment of asthma. Phosphoinositide 3-kinase gamma (PI3Kγ) has been demonstrated to have a significant impact on inflammation and immune responses, thus emerging as a promising therapeutic target for airway inflammatory disease, including asthma. Objective and method There are few studies reporting on the therapeutic effects of PI3Kγ-selective inhibitors in asthma disease. In this study, we investigated the anti-inflammatory and therapeutic effects of PI3Kγ-selective inhibitor JN-KI3 for treating asthma by utilizing both in vivo and in vitro approaches, thereby proving that PI3Kγ-selective inhibitors could be valuable in the treatment of asthma. Results In RAW264.7 macrophages, JN-KI3 effectively suppressed C5a-induced Akt phosphorylation in a concentration-dependent manner, with no discernible toxicity observed in RAW264.7 cells. Furthermore, JN-KI3 can inhibit the PI3K/Akt signaling pathway in lipopolysaccharide-induced RAW264.7 cells, leading to the suppression of transcription and expression of the classical inflammatory cytokines in a concentration-dependent manner. Finally, an ovalbumin-induced murine asthma model was constructed to evaluate the initial therapeutic effect of JN-KI3 for treating asthma. Oral administration of JN-KI3 inhibited the infiltration of inflammatory cells and the expression of T-helper type 2 cytokines in bronchoalveolar lavage fluid, which was associated with the suppression of the PI3K signaling pathway. Lung tissue and immunohistochemical studies demonstrated that JN-KI3 inhibited the accumulation of inflammatory cells around the bronchus and blood vessels, as well as the secretion of mucus and excessive deposition of collagen around the airway. In addition, it reduced the infiltration of white blood cells into the lungs. Conclusion JN-KI3 shows promise as a candidate for the treatment of asthma. Our study also suggests that the inhibitory effects of PI3Kγ on inflammation could offer an additional therapeutic strategy for pulmonary inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Evaluating the anti-inflammatory potential of JN-KI3: the therapeutic role of PI3Kγ- selective inhibitors in asthma treatment

Jia,

Ma,

Xiong

et al. 2024

Preprint

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“…[3,4] They are respectively activated by growth factor receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs). [5][6][7] Hyperactivation of PI3K signaling cascades is one among the most ordinary events in human cancers. [8,9] This strong rationale has led to the search for PI3K inhibitors as therapeutic agents for the treatment of various types of cancer.…”

Section: Introductionmentioning

confidence: 99%

Integration of Multicomplex‐Based Pharmacophore Modeling and Molecular Docking in Machine Learning‐Based Virtual Screening: Toward the Discovery of Novel PI3K Inhibitors

Qiu,

Jia,

Yuan

et al. 2024

Advcd Theory and Sims

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The phosphatidylinositol‐3 kinase (PI3K) pathway is a crucial intracellular signaling pathway within living cells. The hyperactivation of PI3K signaling cascades is a common occurrence in human cancers, rendering PI3K a promising therapeutic target. Although several PI3K inhibitors are already available on the market, the adverse side effects of current therapies continue to highlight the necessity for the development of novel PI3K inhibitors. In this study, a virtual screening strategy employing naïve Bayesian classification (NBC) models, based on multicomplex‐based molecular docking and pharmacophore modeling, is developed. First, the docking accuracy and scoring reliability of four docking software are assessed, and Glide demonstrated higher predictability for PI3K inhibitors. Second, pharmacophore models are generated based on the current reported PI3K‐inhibitor interactions, and five pharmacophore hypotheses displayed significant capability in discriminating active PI3K molecules from inactive ones. Subsequently, three NBC models are constructed based on molecular docking and/or pharmacophore models, and the validation results showed that the NBC model, combining multicomplex‐based molecular docking and pharmacophore, significantly improved the hit rate of virtual screening against PI3K. Finally, the optimal NBC model is employed for virtual screening against the ChEMBL database, leading to the identification of multiple molecules with high potential as active PI3K inhibitors.

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Integration of Consensus‐Based Pharmacophore Mapping and Molecular Docking in Sequential Virtual Screening: Toward the Discovery of Novel PI3Kγ Inhibitors

Yu,

Yuan,

Jia

et al. 2024

ChemistrySelect

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Numerous research studies have demonstrated the significant correlation of phosphatidylinositol‐3 kinase gamma (PI3Kγ) with the onset and progression of various human diseases, highlighting PI3Kγ as a promising therapeutic target. However, PI3Kγ demonstrates considerable similarity with other isoforms in the PI3K family, presenting significant challenges in the creation of PI3Kγ inhibitors. This study presents an ensemble‐based virtual screening approach to discover novel inhibitors targeting PI3Kγ. Eganelisib (IPI‐549) is the sole selective PI3Kγ inhibitor that has progressed to clinical trials, making it a significant model for the advancement of novel PI3Kγ inhibitors. Initially, common feature pharmacophore and receptor–ligand pharmacophore models were independently developed using IPI‐549 and its potent derivatives, in conjunction with the crystal complex of PI3Kγ/IPI‐549. Both qualitative pharmacophore models proved highly effective at distinguishing between active and inactive compounds. Then, four widely utilized docking programs were chosen for assessment, where the Glide_SP mode demonstrated superior predictive accuracy in sampling ligand conformations during binding, effectively distinguishing between PI3Kγ inhibitors and noninhibitors. Finally, a virtual screening protocol was conducted to screen the ChEMBL database, utilizing similarity search, consensus‐based pharmacophore mapping, and sequential molecular docking. This process resulted in the identification of multiple molecules exhibiting notable promise as potent PI3Kγ inhibitors.

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Investigation into the anti-airway inflammatory role of the PI3Kγ inhibitor JN-PK1: An in vitro and in vivo study

Cited by 8 publications

References 55 publications

Evaluating the anti-inflammatory potential of JN-KI3: the therapeutic role of PI3Kγ- selective inhibitors in asthma treatment

Evaluating the anti-inflammatory potential of JN-KI3: the therapeutic role of PI3Kγ- selective inhibitors in asthma treatment

Integration of Multicomplex‐Based Pharmacophore Modeling and Molecular Docking in Machine Learning‐Based Virtual Screening: Toward the Discovery of Novel PI3K Inhibitors

Integration of Consensus‐Based Pharmacophore Mapping and Molecular Docking in Sequential Virtual Screening: Toward the Discovery of Novel PI3Kγ Inhibitors

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