Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs
Disease area: Airway diseases

Abstract

INTRODUCTION Cytokines and chemokines are key modulators of immunological system, playing essential role in inflammation-related diseases, e.g. asthma. Janus kinases (JAKs) are main part of signaling pathways responsible for signal transduction from immune receptors and activation of downstream cytokines' expression. Therefore, selective JAK inhibitors emerge as an attractive strategy in asthma.METHODS AND RESULTS We have designed CPL-407-105 ('105)– a novel small molecule JAK2 inhibitor with high in vitro inhibitory potency (IC₅₀=3nM in recombinant kinase activity assay). Compound exhibited good selectivity versus JAK1 and JAK3 kinases (12- and 25-fold, respectively), as well as versus additional panel of diverse kinases. In cell-based proliferation assays '105 inhibited JAK2-dependent SET-2 cells with IC₅₀ of 320nM, without significant inhibition of JAK-independent HEK293 cells (up to 2,5mM). Western Blot analysis revealed almost complete abrogation of pSTAT3 in HEL cells following treatment with 100nM of '105. Additionally, flow cytometry analysis showed that '105 efficiently decreased pSTAT1 level in IFNg-stimulated CD14⁺ cells (IC₅₀=86nM). '105 also reduced pSTAT5 level in GM-CSF-stimulated CD14⁺ cells and IL-2-stimulated CD3⁺ cells (IC₅₀ of 430nM and 400nM, respectively). Finally, '105 lowered secretion of IFNg, IL-5, IL-6, IL-9, and IL-13 by CD4⁺T cells with IC₅₀ of 100, 10, 500, 30 and 50nM, respectively.CONCLUSION CPL-407-105 exerts anti-inflammatory effect by suppressing cytokine signaling in selected cellular models. Collected data rationalize further evaluation of '105 in advanced in vitro and in vivo models of inflammation-mediated diseases, including asthma.

Rating:

Share or cite this content

Citations should be made in the following way:
P. Gunerka, B. Dymek, D. Zdzalik, M. Mroczkiewicz, J. Lipner, B. Stypik, A. Bujak, P. Grygielewicz, O. Musielak, M. Skupinska, J. Hucz-Kalitowska, K. Dubiel, M. Lamparska-Przybysz, M. Wieczorek, A. Stanczak (Lomianki, Lodz, Warsaw, Poland). Therapeutic potential of CPL-407-105 – Novel potent JAK/STAT pathway inhibitor for the treatment of asthma. Eur Respir J 2014; 44: Suppl. 58, 1509

Member's Comments

No comment yet.

Related content which might interest you: Preclinical characterization of CPL-302-201, a novel, highly potent and selective PI3Kδ inhibitor for the treatment of inflammatory disorders Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs Year: 2014 In vitro profile of the new inhaled pan-JAK inhibitor LAS194046 Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs Year: 2014 In vitro characterization of a novel inhaled PI3Kd inhibitor LAS194223 Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs Year: 2014 Novel, highly potent and selective JAK3 inhibitor disrupting IL-4/IL-13 signaling in asthma therapy Source: International Congress 2015 – New targets and modalities for the treatment of asthma and COPD Year: 2015 Inhibition of JAK/STAT pathway in airway epithelium as a potential targeted therapy of asthma Source: International Congress 2014 – New drugs for asthma, COPD and pulmonary fibrosis Year: 2014 The anti-inflammatory effects of sulforaphane are not mediated by the Nrf2 pathway Source: International Congress 2014 – Novel approaches and evidence for drug development in respiratory diseases Year: 2014 RP6503, a novel and selective PI3K δ/gamma inhibitor, potentiates the effect of steroids in pre-clinical models of COPD Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs Year: 2014 Anti-inflammatory effects of the novel PDE4 inhibitor CHF6001 on virus inducible cytokines Source: International Congress 2014 – Allergy and asthma: novel findings based on human cell biology Year: 2014 Additive anti-inflammatory effect of glucocorticoids and PDE4 inhibitors on COPD CD8 cells Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs Year: 2014 Characterization QAW039 and QAV680, two novel, potent and selective CRTh2 antagonists Source: International Congress 2014 – Allergy and asthma: novel findings based on human cell biology Year: 2014 New inhaled JAK inhibitor LAS194046 inhibits allergen-induced airway inflammation in Brown Norway rats Source: International Congress 2014 – New drugs for asthma, COPD and pulmonary fibrosis Year: 2014 Therapeutic blockade of IL-4 and 13 signaling with dupilumab (SAR231893/REGN668) inhibits key biomarkers in asthma Source: Annual Congress 2013 –Treatment of asthma Year: 2013 AZD5069: Pharmacological profile of a CXCR2 antagonist in development for the treatment of respiratory disorders Source: International Congress 2014 – Novel evidence relating to respiratory treatment development Year: 2014 In vivo efficacy of CHF6001, an inhaled PDE4 inhibitor with a wide therapeutic window Source: International Congress 2014 – Animal models in respiratory drug development Year: 2014 In vitro pharmacological characterization of CHF6001, a novel selective phosphodiesterase 4 (PDE4) inhibitor with a robust anti-inflammatory profile Source: International Congress 2014 – Novel targets and drugs for asthma and COPD Year: 2014 The novel elastase inhibitor BAY 85-8501 provides a new approach in the treatment of pulmonary diseases Source: International Congress 2014 – New drugs for asthma, COPD and pulmonary fibrosis Year: 2014 Anti-inflammatory effects of the novel phosphodiesterase type 4 inhibitor CHF6001 on COPD alveolar macrophages and lung tissue Source: International Congress 2014 – Novel targets and drugs for asthma and COPD Year: 2014 Pre-clinical characterization of RP3128, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders Source: Annual Congress 2013 –New drugs in respiratory medicine Year: 2013 LATE-BREAKING ABSTRACT: Inhibition of RC kinase is a novel therapeutic approach for the treatment of COPD and IPF Source: International Congress 2014 – Latest insights in airway diseases Year: 2014 Redefining the asthma treatment paradigm using a locally administered dual PI3Kgd inhibitor Source: International Congress 2016 – New therapies and therapeutic targets Year: 2016