A first-in-kind MAPK13 inhibitor that can correct stem cell reprogramming and post-injury disease

Abstract

AbstractThe stress kinase MAPK13 (aka p38δ-MAPK) is an attractive entry point for therapeutic intervention because it regulates the structural remodeling that can develop after epithelial barrier 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-4) down-regulates basal-epithelial stem cell reprogramming, structural remodeling, and pathophysiology equivalently toMapk13gene-knockout in mouse and mouse organoid models of post-viral lung disease. This therapeutic benefit persists after stopping treatment as a sign of disease modification and attenuates key aspects of inflammation and remodeling as an indication of disease reversal. Similarly, NuP-4 treatment can directly control cytokine-stimulated growth, immune activation, and mucinous differentiation in human basal-cell organoids. The data thereby provide a new tool and potential fix for long-term stem cell reprogramming after viral injury and related conditions that require MAPK13 induction-activation.New and noteworthyThis study identifies a small-molecule inhibitor for MAPK13 with efficacy and safety in models of the long-term disease that features epithelial stem cell reprogramming towards inflammation and structural remodeling. The present model has direct implications for respiratory disease triggered by viral infection and other inhaled toxins, but the tissue distribution of MAPK13 implies related actions at other epithelial barrier sites. The findings also refine a hypothesis for therapeutic intervention based on proper adjustment of MAPK13 function with a selective kinase inhibitor.