Subject(s)
Benzazepines/adverse effects , Bupropion/adverse effects , Depression/epidemiology , Quinoxalines/adverse effects , Self-Injurious Behavior/epidemiology , Smoking Cessation , Smoking/drug therapy , Suicide/statistics & numerical data , Tobacco Use Cessation Devices/adverse effects , Female , Humans , MaleABSTRACT
Despite the development of a number of efficacious kinase inhibitors, the strategies for rational design of these compounds have been limited by target promiscuity. In an effort to better understand the nature of kinase inhibition across the kinome, especially as it relates to off-target effects, we screened a well-defined collection of kinase inhibitors using biochemical assays for inhibitory activity against 234 active human kinases and kinase complexes, representing all branches of the kinome tree. For our study we employed 158 small molecules initially identified in the literature as potent and specific inhibitors of kinases important as therapeutic targets and/or signal transduction regulators. Hierarchical clustering of these benchmark kinase inhibitors on the basis of their kinome activity profiles illustrates how they relate to chemical structure similarities and provides new insights into inhibitor specificity and potential applications for probing new targets. Using this broad dataset, we provide a framework for assessing polypharmacology. We not only discover likely off-target inhibitor activities and recommend specific inhibitors for existing targets, but also identify potential new uses for known small molecules.
Subject(s)
Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Aurora Kinases , Cluster Analysis , Drug Design , ErbB Receptors/antagonists & inhibitors , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , MAP Kinase Kinase 4/antagonists & inhibitors , Protein Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Reproducibility of Results , Signal Transduction/drug effects , Small Molecule Libraries , Structure-Activity Relationship , Syk Kinase , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
OBJECTIVES: This study explored how war commemorations such as the Cenotaph Service in the UK enable older veterans to benefit from a feeling of integration and belonging gained from both comradeship and acknowledgement from wider society. METHOD: Focus groups preceded by a video clip of the Cenotaph Service with 45 veterans were used to discuss the significance of collective commemorations for older veterans. RESULTS: Findings indicated that social integration and a sense of belonging are fostered both by comradeship and societal support during collective commemorations allowing veterans to reminisce safely. Spontaneous reminiscences involving troubling memories may be processed more easily with the support, social integration and sense of belonging which occurs at collective commemorations. Many Korean War and female World War II veterans felt forgotten and socially isolated, but described gaining vicarious support via collective commemorations. Cohen and Wills' (1985) main-effects and buffering models of social support are used to discuss the findings further. CONCLUSION: Collective commemorations can be important sources of support for many older veterans. Both comradeship and societal support promote social integration and a sense of belonging (main-effects), which enabled reminiscing and processing (buffering) to occur.
