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

Area of Science:

• Cellular and Molecular Biology
• Pharmacology
• Respiratory Medicine

Background:

• Mitogen-activated protein kinase 13 (MAPK13), also known as p38δ-MAPK, plays a critical role in regulating structural remodeling following epithelial barrier injury.
• Current therapeutic options for conditions involving MAPK13 dysregulation are limited due to the lack of selective, safe, and effective inhibitors.

Purpose of the Study:

• To identify and characterize a novel, selective inhibitor of MAPK13.
• To evaluate the therapeutic potential of this inhibitor in preclinical models of lung injury and disease.

Main Methods:

• Structure-based drug design and a screening funnel incorporating cell safety and molecular specificity assessments were employed.
• The efficacy of the identified inhibitor (NuP-4) was assessed in mouse models and organoid cultures of post-viral lung disease.
• Effects on basal-epithelial stem cell reprogramming, structural remodeling, inflammation, and cytokine-stimulated responses were analyzed.

Main Results:

• A first-in-kind MAPK13 inhibitor, NuP-4, was successfully identified.
• NuP-4 demonstrated efficacy equivalent to Mapk13 gene knockout in mouse models, down-regulating stem cell reprogramming, structural remodeling, and pathophysiology.
• Therapeutic benefits, including disease modification and reversal of inflammation and remodeling, persisted after treatment cessation. NuP-4 also controlled cytokine-stimulated growth and differentiation in human basal-cell organoids.

Conclusions:

• NuP-4 represents a promising therapeutic candidate for managing long-term stem cell reprogramming and related pathologies after viral injury.
• This novel inhibitor provides a valuable tool for experimental and potentially clinical applications targeting MAPK13-mediated diseases.
• The findings suggest a potential treatment strategy for conditions characterized by MAPK13 induction and activation.