Y. Zhang, K. Wu, D. Mao, C. A. Iberg, H. Yin-Declue, K. Sun, H. A. Wikfors, S. P. Keeler, M. Li, D. Young, J. Yantis, E. C. Crouch, J. R. Chartock, Z. Han, K. O. Broschat, D. E. Byers, S. L. Brody, A. G. Romero, M. J. Holtzman
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. In a mouse model of severe respiratory viral infection, treatment with this inhibitor (formulated as NuP-4A for intravenous use or Nu4-B for inhaled delivery) did not influence recovery from acute infectious illness, but still down-regulated basal-epithelial stem cell (basal-ESC) hyperplasia/metaplasia and in turn airway inflammation, mucus production, and pathophysiology biomarkers of chronic lung disease. Treatment prevented and reversed disease readouts equivalently to Mapk13 gene-knockout, and this benefit persisted after stopping treatment as a sign of disease modification. Further, NuP-4 treatment even at pM levels directly blocked basal-ESC reprogramming endpoints in organoid and cell-culture models derived from non-disease control and asthma subjects. The results thereby provide a new tool compound and drug candidate for basal-ESC reprogramming towards muco-obstructive lung diseases like asthma and any overlap with COPD and related diseases that depend on overactivity of MAPK13.