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Sci Transl Med. 2018 Nov 21;10(468). pii: eaao2151. doi: 10.1126/scitranslmed.aao2151.

Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma.

Author information

1
Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2
Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Biochemical Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Biology, Charles River Discovery, 8-9 Spire Green Centre, Harlow CM19 5TR, UK.
5
Department of Safety Assessment Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
6
Department of Drug Metabolism and Pharmacokinetics, Charles River Discovery, 8-9 Spire Green Centre, Harlow CM19 5TR, UK.
7
Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
8
Department of Chemistry, Charles River Discovery, 8-9 Spire Green Centre, Harlow CM19 5TR, UK.
9
Department of Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
10
Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. ghilardi@gene.com.

Abstract

Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma.

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