Targeted Inhibition of Select ERK1/2 Functions Mitigates Pathological Features of Asthma in Mice.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) regulate the activity of various transcription factors that contribute to asthma pathogenesis. Although an attractive drug target, broadly inhibiting ERK1/2 is challenging due to unwanted cellular toxicities. We have identified small molecule inhibitors with a benzenesulfonate scaffold that selectively inhibit ERK1/2-mediated activation of Activator Protein-1 (AP-1). Herein, we describe the findings of targeting of ERK1/2-mediated substrate-specific signaling with the small molecule inhibitor, SF-3-030, in a murine model of house dust mite (HDM)-induced asthma. In 8-10 weeks old BALB/c mice, allergic asthma was established by repeated intranasal HDM (25 μg/mouse) instillation for three weeks (5 days/week). A subgroup of mice was prophylactically dosed with 10 mg/kg SF-3-030/DMSO intranasally, 30 min before the HDM challenge. Following the dosing schedule, mice were evaluated for alterations in airway mechanics, inflammation, and markers of airway remodeling. SF-3-030 treatment significantly attenuated HDM-induced elevation of distinct inflammatory cell types and cytokine levels in bronchoalveolar lavage and IgE levels in the lungs. Histopathological analysis of lung tissue sections revealed diminished HDM-induced pleocellular peribronchial inflammation, mucus cell metaplasia, collagen accumulation, thickening of ASM mass, and expression of markers of cell proliferation (Ki-67 and cyclin D1) in mice treated with SF-3-030. Further, SF-3-030 treatment attenuated HDM-induced airway hyperresponsiveness in mice. Finally, mechanistic studies using transcriptome and proteome analyses suggest inhibition of HDM-induced genes involved in inflammation, cell proliferation, and tissue remodeling by SF-3-030. These preclinical findings demonstrate that function-selective inhibition of ERK1/2 signaling mitigates multiple features of asthma in a murine model.