Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Emphysema.

The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and alpha 1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces loss of lung function in SM-exposed mice. However, the PP2A activator tricyclic sulfonamide compound previously utilized, DBK-1154, has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792 (792), to DBK-1154 (1154) for the treatment of SM-induced emphysema. 792 was also tested in human bronchial epithelial (HBE) cells and the AAT deficiency mouse model, Serpina1a-e knockout mice. HBE cells were treated with 792 or 1154, and cell viability, PP2A activity, and MAP kinase phosphorylation status were examined. Wild-type mice received either vehicle, 1154 or 792 by oral administration in the last 2 months of 4 months of SM exposure. 8-month-old Serpina1a-e knockout mice daily received 792 for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with 792 or 1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of PP2A activity, occurring in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.