Airway inflammatory diseases, such as asthma, are characterized by inflammation, airway remodeling and hyperresponsiveness resulting in severe bronchoconstriction. Asthma pathogenesis is driven by inflammatory mediators that act on immune cells and resident airways cells through receptors that regulate signaling molecules and gene expression. Transcriptional activation is a common end point in the signaling elicited by multiple cytokines in target cells. The transcription factor, Activator Protein (AP)-1 is activated by mitogen-activated protein (MAP) kinases, such as ERK1/2, and is known to mediate airway inflammation, airway smooth muscle (ASM) remodeling, and mucus production, and therefore is an attractive anti-asthma therapeutic target. Current kinase inhibitors used as anti-inflammatory or anti-oncogenic agents target ATP binding or catalytic sites and block all enzymatic activity. These drugs invariably lead to drug resistance or toxicity due to lack of specificity. Using advanced computer-aided drug design methods we have identified a novel thienyl benzenesulfonate chemical scaffold that selectively inhibits ERK1/2-mediated AP-1 activity taking advantage of the structural requirements of ERK1/2 and specific substrates. These novel substrate- specific inhibitors of ERK1/2 bind the F-recruitment site (FRS) of ERK1/2, which mediates interactions with AP-1 substrates containing an F-site or FXF motif. Functional validation studies demonstrate that the compounds inhibit specific kinase functions associated with disease while preserving ERK1/2 functions in normal cells. In this proposal we aim at evaluating the efficacy of newly developed small molecule inhibitors of ERK1/2 in mitigating features of asthma.
Aim 1 studies will establish the effect of substrate-specific inhibitors of ERK1/2 on human ASM cell growth and secretion of extracellular matrix, chemokines and cytokines.
Aim 2 studies will ascertain specificity and signaling mechanisms modulated by these compounds. Finally, we will employ an integrated mouse model of asthma to determine the in vivo efficacy of ERK1/2 inhibitors in mitigating allergen-induced airway inflammation, remodeling, mucus production and airway hyperresponsiveness. Preliminary data suggest that the compounds inhibit mitogen-induced ASM cell growth and AP-1 activation. Importantly, the compounds did not inhibit growth factor-induced phosphorylation of ERK1/2 or Akt further confirming the specificity of targeting downstream ERK1/2 substrates in ASM. Considering the ubiquitous expression and functional role of ERK1/2-induced activation of AP-1 in asthma pathogenesis, we predict that novel substrate specific inhibitors of ERK1/2 mitigate multiple features of asthma in the animal model. These studies will provide important pre-clinical data to advance a novel class of small molecule inhibitors targeting a versatile signaling molecule as anti-asthma therapies.
Allergen-induced inflammation and an increase in the amount of airway smooth muscle in the lung occur in chronic diseases such as asthma and chronic obstructive pulmonary disease (COPD) and contribute to disease progression and severity. Recently we have identified a novel class of compounds that can inhibit signaling molecules critical in the pathogenesis of asthma Studies proposed in this application will determine if and how these new compounds inhibit pathological features of asthma including airway smooth muscle growth and inflammation. If successful, the findings from the proposed studies will pave way for the development of a new class of anti-asthma drugs.
| Eapen, Mathew S; Kota, Anudeep; Vindin, Howard et al. (2018) Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease. Clin Sci (Lond) 132:1615-1627 |
| Nayak, Ajay P; Deshpande, Deepak A; Penn, Raymond B (2018) New targets for resolution of airway remodeling in obstructive lung diseases. F1000Res 7: |
