A potent MAPK13-14 inhibitor prevents airway inflammation and mucus production

• Published in: American journal of physiology. Lung cellular and molecular physiology 2023-12, Vol.325 (6), p.L726-L740
• Main Authors: Keeler, Shamus P, Wu, Kangyun, Zhang, Yong, Mao, Dailing, Li, Ming, Iberg, Courtney A, Austin, Stephen R, Glaser, Samuel A, Yantis, Jennifer, Podgorny, Stephanie, Brody, Steven L, Chartock, Joshua R, Han, Zhenfu, Byers, Derek E, Romero, Arthur G, Holtzman, Michael J
• Format: Article
• Language: English
• Subjects: Allergic diseases; Animals; Cell culture; Clinical trials; Cytokines; Cytokines - metabolism; Disease; Epithelial cells; Epithelium; Humans; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inhibitors; Kinases; MAP kinase; Mitogen-Activated Protein Kinase 13 - metabolism; Mitogen-Activated Protein Kinase 14 - metabolism; Morbidity; Mucus; Mucus - metabolism; Organoids; Public health; Pulmonary Disease, Chronic Obstructive - metabolism; Respiration; Respiratory diseases; Respiratory tract diseases; Swine; Swine, Miniature - metabolism
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00183.2023

Common respiratory diseases continue to represent a major public health problem, and much of the morbidity and mortality is due to airway inflammation and mucus production. Previous studies indicated a role for mitogen-activated protein kinase 14 (MAPK14) in this type of disease, but clinical trials are unsuccessful to date. Our previous work identified a related but distinct kinase known as MAPK13 that is activated in respiratory airway diseases and is required for mucus production in human cell-culture models. Support for MAPK13 function in these models came from effectiveness of versus gene-knockdown and from first-generation MAPK13-14 inhibitors. However, these first-generation inhibitors were incompletely optimized for blocking activity and were untested in vivo. Here we report the next generation and selection of a potent MAPK13-14 inhibitor (designated NuP-3) that more effectively downregulates type-2 cytokine-stimulated mucus production in air-liquid interface and organoid cultures of human airway epithelial cells. We also show that NuP-3 treatment prevents respiratory airway inflammation and mucus production in new minipig models of airway disease triggered by type-2 cytokine challenge or respiratory viral infection. The results thereby provide the next advance in developing a small-molecule kinase inhibitor to address key features of respiratory disease. This study describes the discovery of a potent mitogen-activated protein kinase 13-14 (MAPK13-14) inhibitor and its effectiveness in models of respiratory airway disease. The findings thereby provide a scheme for pathogenesis and therapy of lung diseases [e.g., asthma, chronic obstructive pulmonary disease (COPD), Covid-19, postviral, and allergic respiratory disease] and related conditions that implicate MAPK13-14 function. The findings also refine a hypothesis for epithelial and immune cell functions in respiratory disease that features MAPK13 as a possible component of this disease process.