A new MAPK13-guided inhibitor for respiratory inflammation and mucus production

Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Our previous work identified a mitogen-activated protein kinase (MAPK) known as MAPK13 that is activated in airway disease and is required for mucus production in human cell-culture models. However, only weak first-generation MAPK13 inhibitors were made to confirm gene-knockdown function, and there was no extension to effectiveness in vivo. Here we report the discovery of a first-in-class MAPK13 inhibitor (designated NuP-3) that down-regulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment effectively attenuates respiratory inflammation and mucus production in new minipig models of airway disease after type-2 cytokine challenge or respiratory viral infection. Treatment also down-regulates biomarkers linked to basal-epithelial stem cell activation as an upstream site for target engagement. The results thereby provide proof-of-concept for a novel small-molecule kinase inhibitor to modify as yet uncorrected features of respiratory airway disease including stem cell reprogramming towards inflammation and mucus production.

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