Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation

Abstract

Increased airway smooth muscle (ASM) cell mass and secretory functions are characteristics of airway inflammatory diseases, such as asthma. To date, there are no effective therapies to combat ASM cell proliferation, which contributes to bronchoconstriction and airway obstruction. Growth factors such as platelet-derived growth factor (PDGF) and the activation of the ERK1/2 are major regulators of ASM cell proliferation and airway remodeling in asthma. However, given the ubiquitous expression and multiple functions of ERK1/2, complete inhibition of ERK1/2 using ATP-competitive inhibitors may lead to unwanted off-target effects. Alternatively, we have identified compounds that are designed to target substrate docking sites and act as function-selective inhibitors of ERK1/2 signaling. Here, we show that both function-selective and ATP-competitive ERK1/2 inhibitors are effective at inhibiting PDGF-mediated proliferation, collagen production, and IL-6 secretion in ASM cells. Proteomic analysis revealed that both types of inhibitors had similar effects on reducing proteins related to TGF-β and IL-6 signaling that are relevant to airway remodeling. However, function-selective ERK1/2 inhibitors caused fewer changes in protein expression compared with ATP-competitive inhibitors. These studies provide a molecular basis for the development of function-selective ERK1/2 inhibitors to mitigate airway remodeling in asthma with defined regulation of ERK1/2 signaling.—Defnet, A. E., Huang, W., Polischak, S., Yadav, S. K., Kane, M. A., Shapiro, P., Deshpande, D. A. Effects of ATP-competitive and function-selective ERK inhibitors on airway smooth muscle cell proliferation. FASEB J. 33, 10833–10843 (2019). www.fasebj.org.