Molecular mechanisms of pulmonary response progression in crystalline silica exposed rats

<p>An understanding of the mechanisms underlying diseases is critical for their prevention. Excessive exposure to crystalline silica is a risk factor for silicosis, a potentially fatal pulmonary disease. Male Fischer 344 rats were exposed by inhalation to crystalline silica (15 mg/m³, six hours/day, five days) and pulmonary response was determined at 44 weeks following termination of silica exposure. Additionally, global gene expression profiling in lungs and BAL cells and bioinformatic analysis of the gene expression data were done to understand the molecular mechanisms underlying the progression of pulmonary response to silica. A significant increase in lactate dehydrogenase activity and albumin content in BAL fluid (BALF) suggested silica-induced pulmonary toxicity in the rats. A significant increase in the number of alveolar macrophages and infiltrating neutrophils in the lungs and elevation in monocyte chemoattractant protein-1 (MCP-1) in BALF suggested the induction of pulmonary inflammation in the silica exposed rats. Histological changes in the lungs included granuloma formation, type II pneumocyte hyperplasia, thickening of alveolar septa and positive response to Masson’s trichrome stain. Microarray analysis of global gene expression detected 94 and 225 significantly differentially expressed genes in the lungs and BAL cells, respectively. Bioinformatic analysis of the gene expression data identified significant enrichment of several disease and biological function categories and canonical pathways related to pulmonary toxicity, especially inflammation. Taken together, these data suggested the involvement of chronic inflammation as a mechanism underlying the progression of pulmonary response to exposure of rats to crystalline silica at 44 weeks following termination of exposure.</p

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>

Discovery of a Potent, Orally Bioavailable PI4KIIIβ Inhibitor (UCB9608) Able To Significantly Prolong Allogeneic Organ Engraftment <i>in Vivo</i>

The primary target of a novel series of immuno­suppressive 7-piperazin-1-yl­thiazolo­[5,4-<i>d</i>]­pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIβ. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physico­chemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound <b>22</b> was initially identified and profiled <i>in vivo</i>, before further modifications led to the discovery of <b>44</b> (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmaco­kinetic profile. A co-crystal structure of <b>44</b> with PI4KIIIβ was solved, confirming the binding mode of this class of inhibitor. The much-improved <i>in vivo</i> profile of <b>44</b> positions it as an ideal tool compound to further establish the link between PI4KIIIβ inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses <i>in vivo</i>