Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

J Pharmacol Exp Ther. 2019 Aug;370(2):137-147. doi: 10.1124/jpet.119.256263. Epub 2019 May 13.

Abstract

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Allergens / immunology*
  • Animals
  • Asthma / drug therapy*
  • Asthma / immunology*
  • Asthma / metabolism
  • Asthma / pathology
  • Inflammation / drug therapy
  • Isoenzymes / antagonists & inhibitors
  • Janus Kinase Inhibitors / administration & dosage
  • Janus Kinase Inhibitors / pharmacokinetics
  • Janus Kinase Inhibitors / pharmacology*
  • Janus Kinase Inhibitors / therapeutic use
  • Janus Kinases / antagonists & inhibitors*
  • Male
  • Nitriles / administration & dosage
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology*
  • Nitriles / therapeutic use
  • Phosphoproteins / metabolism*
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / drug effects
  • Time Factors

Substances

  • Allergens
  • Isoenzymes
  • Janus Kinase Inhibitors
  • Nitriles
  • Phosphoproteins
  • Piperidines
  • Pyrimidines
  • STAT Transcription Factors
  • Janus Kinases