@article {BoehmeP2822, author = {Stefen Boehme and Ana Coelho and Cory Hogaboam and Tai Wei Ly and Kevin Bacon and Jon Athanacio}, title = {Late-breaking abstract: Inhibition of RC kinase is a novel therapeutic approach for the treatment of COPD and IPF}, volume = {44}, number = {Suppl 58}, elocation-id = {P2822}, year = {2014}, publisher = {European Respiratory Society}, abstract = {RC kinase is a novel serine/threonine kinase, expressed predominantly by pulmonary macrophage and type II bronchial epithelial cells. Examination of BAL macrophage mRNA isolated from COPD and IPF patients showed increased expression of RC kinase compared to normal smokers and non-smoking patients. In vitro studies showed an upregulation of RC kinase upon cell stress, including oxidative stress. This correlated with an increase of NF-kb activity and IL-8 production that could be inhibited by RC kinase siRNA or small molecule antagonists. Biochemical analysis revealed that RC kinase is predominantly a nuclear protein and interacts with p27, a CDK inhibitor protein, and the NF-kb pathway. We have developed specific, extremely potent and orally administered small molecule antagonists of RC kinase with a favorable ADME profile. Mice treated with these compounds in an acute model of COPD showed significant reductions in the number of BAL neutrophils and the chemokine KC. Similar results were seen in mice treated with RC kinase siRNA. In a chronic (5 month) cigarette smoke exposure model, the small molecule antagonists were effective in both reducing inflammation and significantly limiting alveoli destruction. Inhibition of RC kinase in an acute cigarette smoke and viral exacerbation model reduced BAL neutrophils, inhibited cytokines such as IL-6 and significantly reduced viral titers. In a murine xenograft model of IPF, inhibition of RC kinase by small molecules or siRNA caused significant reductions in the inflammatory infiltrate, hydroxyproline production and collagen deposition in the lungs. Additionally, mRNA levels of collagens 1 \& 3, smooth muscle actin and fibronectin were also reduced.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/44/Suppl_58/P2822}, eprint = {https://erj.ersjournals.com/content}, journal = {European Respiratory Journal} }