Inhibition of Pim1 Kinase Activation Attenuates Allergen-Induced Airway Hyperresponsiveness and Inflammation

Abstract

Pim kinases are a family of serine/threonine kinases whose activity can be induced by cytokines involved in allergy and asthma. These kinases play a role in cell survival and proliferation, but have not been examined, to the best of our knowledge, in the development of allergic disease. This study sought to determine the role of Pim1 kinase in the development of allergic airway responses. Mice were sensitized and challenged with antigen (primary challenge), or were sensitized, challenged, and rechallenged with allergen in a secondary model. To assess the role of Pim1 kinase, a small molecule inhibitor was administered orally after sensitization and during the challenge phase. Airway responsiveness to inhaled methacholine, airway and lung inflammation, cell composition, and cytokine concentrations were assessed. Lung Pim1 kinase concentrations were increased after ovalbumin sensitization and challenge. In the primary allergen challenge model, treatment with the Pim1 kinase inhibitor after sensitization and during airway challenges prevented the development of airway hyperresponsiveness, eosinophilic airway inflammation, and goblet cell metaplasia, and increased Th2 cytokine concentrations in bronchoalveolar fluid in a dose-dependent manner. These effects were also demonstrated after a secondary allergen challenge, where lung allergic disease was established before treatment. After treatment with the inhibitor, a significant reduction was evident in the number of CD4 1 and CD8 1 T cells and concentrations of cytokines in the airways. The inhibition of Pim1 kinase was effective in preventing the development of airway hyperresponsiveness, airway inflammation, and cytokine production in allergensensitized and allergen-challenged mice. These data identify the important role of Pim1 kinase in the full development of allergeninduced airway responses.

Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing TH2 and TH17 T-cell differentiation

“…The specificity of AR460770 for Pim1 kinase was previously demonstrated. 9 Administration of the inhibitor to sensitized WT mice resulted in a dose-dependent inhibitory effect on intestinal allergy induction; 30 to 100 mg/kg of the inhibitor fully prevented the development of diarrhea and symptoms in PE-sensitized and challenged WT mice. In contrast, inhibitor treatment of Runx3 +/− mice resulted in reduced inhibitory effects; 30 to 100 mg/kg of the inhibitor partially inhibited diarrhea and symptoms in Runx3 +/− mice.…”

“…9 PE-sensitized and challenged mice received different doses (0-100 mg/kg) of the inhibitor by means of gavage and based on earlier experiments. 9 For more information, see the Methods section in this article's Online Repository.…”

“…7 Pim1 kinase expression was upregulated in the lungs of mice after sensitization and challenge with allergen. 9 …”

Potential Use of Selective and Nonselective Pim Kinase Inhibitors for Cancer Therapy

“…The benzo [4,5] thieno [3,2-d]pyrimidin-4(3H)-ones (7, Figure 3) discussed above also belong to this class of molecules. Using structure-based drug design, scientists at Exelixis converged toward a very similar series of molecules in which the sulfur atom of the scaffold was replaced by an oxygen atom.…”

“…Another promising class of Pim inhibitors is represented by benzo [4,5] thieno [3,2-d]pyrimidin-4(3H)-one 7, analogue of a series of potent pan-Pim kinase inhibitors discovered by scientists at Abbott. 38 Starting from a novel HTS hit, this group used structure-based drug design to optimize the series and carry out extensive SAR studies.…”