A first-in-kind MAPK13 inhibitor corrects stem cell reprogramming and muco-obstructive lung disease

The stress kinase MAPK13 (aka p38delta-MAPK) is an attractive entry point for therapeutic intervention because it regulates the structural remodeling that can develop after epithelial injury in the lung and likely other tissue sites. However, a selective, safe, and effective MAPK13 inhibitor is not yet available for experimental or clinical application. Here we identify a first-in-kind MAPK13 inhibitor using structure-based drug design combined with a screening funnel for cell safety and molecular specificity. This inhibitor (designated NuP-4A for intravenous or Nu4-B for inhaled delivery) down-regulates basal-epithelial stem cell reprogramming, structural remodeling, and pathophysiology equivalently to Mapk13 gene-knockout in mouse and mouse organoid models of muco-obstructive lung disease after viral infection. Treatment prevents and reverses disease biomarkers, and this benefit persists after stopping treatment as a sign of disease modification. Similarly, NuP-4 treatment can directly control stimulated growth, immune activation, and mucinous differentiation in human basal-cell organoids. The results thereby provide a new tool and potential correction for stem cell reprogramming towards muco-obstructive lung diseases like asthma and COPD and related diseases that might depend on overactivation of MAPK13.

This study identifies a highly selective and potent small-molecule inhibitor for stress kinase MAPK13 in controlling the basal-epithelial stem cell response to viral infection and the consequent development of muco-obstructive lung disease. The present model has direct implications for diseases like asthma and COPD that are triggered by respiratory viruses and other inhaled toxins. Further, the tissue distribution of MAPK13 implies related actions at other epithelial sites. The findings also refine a hypothesis for therapeutic intervention based on proper scaling of MAPK13 function including precise down-regulation with a highly selective MAPK13 inhibitor.