Preclinical characterization of CPL302-253, a selective inhibitor of PI3Kδ, as the candidate for the inhalatory treatment and prevention of Asthma

Gunerka, Paweł; Gala, Kamila; Banach, Martyna; Dominowski, Jakub; Hucz-Kalitowska, Joanna; Mulewski, Krzysztof; Hajnal, A.; Mikus, Endre G.; Smuga, Damian; Zagozda, Marcin; Dubiel, Krzysztof; Pieczykolan, Jerzy; Zygmunt, Beata M.; Wieczorek, Maciej

doi:10.1371/journal.pone.0236159

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Instead, this phosphorylation may lead to the expression of a distinct set of target genes [ 122 , 123 ]. In addition, the PI3K/Akt signaling pathway contains upstream molecules of NF-κB, which has a regulatory role in allergic asthma [ 97 , 124 , 125 , 126 , 127 ].…”

Section: Discussionmentioning

confidence: 99%

“…The lung epithelial cells and macrophages over-expressed extensive inflammatory chemokines and cytokines due to LPS stimulation, which leads to the recruitment of various immune cells and subsequently causes excessive lung and airway inflammation seen in asthmatics. The data in the gray boxes were cited from [ 16 , 17 , 18 , 20 , 21 , 32 , 33 , 39 , 50 , 51 , 52 , 53 , 55 , 58 , 59 , 63 , 64 , 65 , 68 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 82 , 83 , 84 , 85 , 86 , 97 , 115 , 116 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 130 , 133 , 134 ]. OA treatments significantly suppressed the data in the green boxes.…”

Section: Figurementioning

confidence: 99%

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Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro

Hong

Lee

2022

Life

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In this study, we aimed to evaluate the anti-inflammatory effects and mechanisms of CP and OA treatments in LPS-stimulated lung epithelial cells on overall chemokines and their receptors using PCR arrays. In addition, we aimed to confirm those effects and mechanisms in LPS-stimulated lung macrophages on some chemokines and cytokines. In our study, CP treatments significantly inhibited the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL6, CCL9, CCL11, CCL17, CCL20, CXCL1, CXCL2, CXCL3, CXCL5, CXCL7, CXCL10, TNF-α, and IL-6, while markedly suppressing NF-κB p65 nuclear translocation and the phosphorylations of PI3K p55, Akt, Erk1/2, p38, and NF-κB p65 in LPS-stimulated lung epithelial cells. CP treatments also significantly decreased the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, and CXCL2, while markedly inhibiting phospho-PI3K p55 and iNOS expression in LPS-stimulated lung macrophages. Likewise, OA treatments significantly suppressed the inflammatory mediators CCL2, CCL3, CCL4, CCL5, CCL8, CCL11, CXCL1, CXCL3, CXCL5, CXCL7, CXCL10, CCRL2, TNF-α, and IL-6, while markedly reducing the phosphorylations of PI3K p85, PI3K p55, p38, JNK, and NF-κB p65 in LPS-stimulated lung epithelial cells. Finally, OA treatments significantly inhibited the inflammatory mediators CCL2, CCL5, CCL17, CXCL1, CXCL2, TNF-α, and IL-6, while markedly suppressing phospho-PI3K p55, iNOS, and Cox-2 in LPS-stimulated lung macrophages. These results prove that CP and OA treatments have anti-inflammatory effects on the inflammatory chemokines and cytokines by inhibiting pro-inflammatory mediators, including PI3K, Akt, MAPKs, NF-κB, iNOS, and Cox-2. These findings suggest that CP and OA are potential chemokine-based therapeutic substances for treating the lung and airway inflammation seen in allergic disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro

Hong

Lee

2022

Life

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“…First-phase metabolic stability was investigated in vitro using human (HLM) and mouse (MLM) liver microsomes (Gibco, Thermo Fisher Scientific) as described in Gunerka et al, 2020, with some modifications [ 53 ]. Verapamil and warfarin were used as high and low clearance reference compounds, respectively.…”

Section: Methodsmentioning

confidence: 99%

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists

et al. 2021

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TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF’s action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 μM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.

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Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer

Popiel,

Stańczak,

Skupińska

et al. 2024

Front. Oncol.

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Fibroblast Growth Factor Receptors (FGFRs) are a family of receptor tyrosine kinases expressed on a plethora of cell membranes. They play crucial roles in both embryonic development and adult tissue functions. There is an increasing amount of evidence that FGFR-mediated oncogenesis is mainly related to gene amplification, activating mutations, or translocation in tumors of various histological types. Dysregulation of FGFRs has been implicated in a wide variety of neoplasms, such as bladder, gastric, and lung cancers. Given their functional significance, FGFRs emerge as promising targets for cancer therapy. Here, we introduce CPL304100, an innovative and highly potent FGFR1–3 kinase inhibitor demonstrating excellent in vitro biological activity. Comprehensive analyses encompassed kinase assays, cell line evaluations, PK/PD studies surface plasmon resonance studies, molecular docking, and in vivo testing in mouse xenografts. CPL304110 exhibited a distinctive binding profile to FGFR1/2/3 kinase domains, accompanied by a good safety profile and favorable ADMET parameters. Selective inhibition of tumor cell lines featuring active FGFR signaling was observed, distinguishing it from cell lines lacking FGFR aberrations (FGFR1, 2, and 3). CPL304110 demonstrated efficacy in both FGFR-dependent cell lines and patient-derived tumor xenograft (PDTX) in vivo models. Comparative analyses with FDA-approved FGFR inhibitors, erdafitinib and pemigatinib, revealed certain advantages of CPL304110 in both in vitro and in vivo assessments. Encouraging preclinical results led the way for the initiation of a Phase I clinical trial (01FGFR2018; NCT04149691) to further evaluate CPL304110 as a novel anticancer therapy.

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Preclinical characterization of CPL302-253, a selective inhibitor of PI3Kδ, as the candidate for the inhalatory treatment and prevention of Asthma

Cited by 4 publications

References 33 publications

Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro

Anti-Inflammatory Effects of Cicadidae Periostracum Extract and Oleic Acid through Inhibiting Inflammatory Chemokines Using PCR Arrays in LPS-Induced Lung inflammation In Vitro

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists

Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer

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