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

Abstract

Introduction: Janus kinase (JAK) is a novel anti-inflammatory target for asthma and COPD. In our internal discovery efforts we have identified LAS194046 as a potent pan-JAK inhibitor that blocks multiple cytokine receptor signaling depending on JAK1, JAK2, JAK3 and Tyk2.Aim: To characterize the enzymatic and cellular potency and the selectivity of JAK inhibitor LAS194046 compared with the reference compounds ruxolitinib and tofacitinib.Methods: JAK1, JAK2, JAK3 and Tyk2 kinase activities were assessed by HTRF assays. Inhibition of phosphorylation of downstream STAT (pSTAT) upon cytokine stimulation in human PBMCs was measured by flow cytometry: IL4-induced pSTAT6 (via JAK1/3), GM-CSF-induced pSTAT5 (via JAK2/2), IFNa-induced pSTAT1 (via JAK1/Tyk2) and IL12-induced pSTAT4 (via Jak2/Tyk2).The selectivity profile was assessed at 10 mM in a Millipore Kinase Profiler panel comprising 38 kinases.Results: LAS194046 inhibits JAK1, JAK2 and JAK3 kinase activity with similar potency to ruxolitinib and tofacitinib (IC₅₀:>10 nM). The compound also inhibits Tyk2 with higher potency than tofacitinib (8-fold) and lower than ruxolitinib (15-fold less). In PBMCs the three compounds inhibits JAK1/3 and JAK1/Tyk2 assays (IC₅₀< 50 nM). LAS194046 and ruxolitinib inhibits JAK2/2 (IC₅₀<40 nM) with higher potency than tofacitinib (7-fold). LAS194046 inhibits JAK2/Tyk2 assay with lower potency than ruxolitinib. No relevant off-target activities were identified.Conclusions: LAS194046 is a potent pan-JAK inhibitor, that inhibits JAK1/2/3 and Tyk2 activities and associated cytokine receptor signaling. The promising in vitro profile of LAS194046 supports to further characterize its ADME properties and in vivo efficacy by inhaled route.

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I. Ramis, C. Carreño, A. Orellana, M. Maldonado, J. Bach, M. Miralpeix (Sant Feliu de Llobregat, Spain). In vitro profile of the new inhaled pan-JAK inhibitor LAS194046. Eur Respir J 2014; 44: Suppl. 58, 1508

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