Novel Modulators of ERK1/2 signaling relevance to lung fibroblasts and airway remodeling in asthma

Abstract ID 131182 Poster Board 371 Asthma is a lung airway obstructive disease that affects around 300 million people worldwide. The pathophysiology of asthma includes tissue inflammation, hyperplasia and hyperresponsiveness of the airway smooth muscle, airway remodeling and excess mucus formation. With the emerging knowledge of heterogeneity of asthma, current therapies that target symptoms of the disease, such as airway hyperactivity and inflammation, are not effective for all types of asthma. In addition, there are currently no effective therapies to prevent airway remodeling in asthma. Our lab is focused on the role of the extracellular signal-regulated kinases ERK1/2 and regulation of substrates in lung cells involved in airway remodeling. Previously, we have identified ERK1/2 targeted compounds that selectively inhibit the activator protein-1 (AP-1) transcription factor complex and airway smooth muscle cell proliferation, which has been implicated in airway remodeling. We hypothesize that these compounds will also affect lung fibroblasts. In these studies, we have performed structure-activity relationship studies on the lead compound consisting of a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold. The activity of ERK1/2 following growth factor stimulation was measured in lung fibroblasts using immunoblotting. Additionally, proliferation assays were performed to measure the efficacy of the compounds. We have identified new analogues that are potent inhibitors of lung fibroblast proliferation and are predicted to have better lung absorption, distribution, metabolism, and excretion (ADME) properties compared to the parent compound. NIH- R61HL168723 Optimizing function-selective ERK1/2 inhibitors for reducing AP-1-mediated airway pathology in asthma