TY - JOUR T1 - Therapeutic potential of CPL-407-105 – Novel potent JAK/STAT pathway inhibitor for the treatment of asthma JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P1509 AU - Pawel Gunerka AU - Barbara Dymek AU - Daria Zdzalik AU - Michal Mroczkiewicz AU - Joanna Lipner AU - Bartosz Stypik AU - Anna Bujak AU - Paulina Grygielewicz AU - Olga Musielak AU - Monika Skupinska AU - Joanna Hucz-Kalitowska AU - Krzysztof Dubiel AU - Monika Lamparska-Przybysz AU - Maciej Wieczorek AU - Aleksandra Stanczak Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P1509.abstract N2 - 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 2,5μM). 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 IFNγ-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 IFNγ, 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. ER -