<p>Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD</p>

Abstract

Background: Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dualspecificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood. Objectives: The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance. Methods: Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients. The anti-inflammatory effect of MEK1/2 inhibition was assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages. The effect of MEK1/2 inhibition on bacterial clearance was assessed using Staphylococcus aureus killing assays with RAW 264.7 macrophage cell line and human neutrophils. Results: We report here MEK1/2 pathway activation demonstrated by increased pERK1/2 staining in bronchial epithelium and by the presence of MEK gene activation signature in sputum samples from COPD patients. Inhibition of MEK1/2 resulted in a superior antiinflammatory effect in human alveolar macrophages in comparison to a p38 inhibitor. Furthermore, MEK1/2 inhibition led to an increase in bacterial killing in human neutrophils and RAW 264.7 cells that was not observed with the p38 inhibitor. Conclusion: Our data demonstrate the activation of MEK1/2 pathway in COPD and highlight a dual function of MEK1/2 inhibition in improving host defense responses whilst also controlling inflammation.

MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection

“…Studies have shown that MEKi trametinib in a cecal puncture-sepsis model reduced cytokines as well as kidney, liver, and muscle injury in vivo [ 52 ]. In chronic obstructive pulmonary disease (COPD), MEK1/2 inhibition has an anti-inflammatory effect in human alveolar macrophages while promoting increased bacterial killing in neutrophils [ 53 ]. MEKi selumetinib has been previously observed to reduce IL-6 levels in a Lewis lung carcinoma model although it did not protect against cachexia [ 54 ].…”

Variations in the Antioxidant, Anticancer, and Anti-Inflammatory Properties of Different Rosa rugosa Organ Extracts

“…In LPS-stimulated macrophage cells, toll-like receptor-4 (TLR4) activates mitogenactivated protein kinase (MAPK) cascades, including the MEK/ERK signaling pathway, which plays an essential role in the production of pro-inflammatory mediators [27]. Therefore, the MEK/ERK signaling pathway has been proposed as a potential therapeutic target for controlling inflammation [28,29]. Next, the activation of MEK1/2 and ERK1/2 was analyzed to investigate the inhibitory effect of LE on MEK/ERK signaling in LPS-stimulated RAW 264.7 cells.…”

Fragment-Based Discovery of Novel Allosteric MEK1 Binders

“…The authors declare no competing financial interest. Accession Codes: Atomic coordinates and structure factors have been deposited in the Protein Data Bank with accession codes 7B7R (4), 7B3M (6), 7B94 (9), and 7B9L (23).…”

“…While the major focus of MEK1 as a therapeutic target has been for oncology indications, there is additional interest in the inhibition of this enzyme for the treatment of chronic obstructive pulmonary disease (COPD). − While approved MEK1 inhibitors have proven to be highly effective in oncology settings, the differing requirements of COPD small-molecule therapeuticsfor example, the desire for rapid systemic clearance of an inhaled drugsuggest that new MEK1 inhibitors with differing physicochemical and ADME properties may be needed, while retaining the benefits of an allosteric binding mode. Interestingly, fragment-based methods have been employed as a means to discover allosteric inhibitors of various protein classes, − including kinases, , yet reports of fragment screens targeting MEK1, while successful, have yielded binders of the orthosteric ATP binding site only. , As a consequence, we set out to design and execute a fragment-based screening campaign targeting MEK1 specifically designed to find novel, allosteric inhibitors.…”