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

Zhang, Y.; Wu, K.; Mao, D.; Iberg, C. A.; Yin-Declue, H.; Sun, K.; Wikfors, H. A.; Keeler, S. P.; Li, M.; Young, D.; Yantis, J.; Crouch, E. C.; Chartock, J. R.; Han, Z.; Byers, D. E.; Brody, S. L.; Romero, A. G.; Holtzman, M. J.

doi:10.1101/2024.08.21.608990

bioRxiv · 10.1101/2024.08.21.608990

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

Zhang, Y.·Wu, K.·Mao, D.·Iberg, C. A.·Yin-Declue, H.·Sun, K.·Wikfors, H. A.·Keeler, S. P.·Li, M.·Young, D.·Yantis, J.·Crouch, E. C.·Chartock, J. R.·Han, Z.·Byers, D. E.·Brody, S. L.·Romero, A. G.·Holtzman, M. J.

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Abstract

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.

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Zhang, Y., Wu, K., Mao, D., Iberg, C. A., Yin-Declue, H., Sun, K., Wikfors, H. A., Keeler, S. P., Li, M., Young, D., Yantis, J., Crouch, E. C., Chartock, J. R., Han, Z., Byers, D. E., Brody, S. L., Romero, A. G., Holtzman, M. J.. 2024-08-22. A first-in-kind MAPK13 inhibitor that can correct stem cell reprogramming and post-injury disease. https://doi.org/10.1101/2024.08.21.608990

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