Recent Advances in Kinase Drug Discovery Part I: the Editors’ Take

This special issue on Advances in Kinase Drug Discovery provides a selection of research articles and topical reviews covering all aspects of drug discovery targeting the phosphotransferase enzyme family [...

Small molecule ERK5 kinase inhibitors paradoxically activate ERK5 signalling: be careful what you wish for...

ERK5 is a protein kinase that also contains a nuclear localisation signal and a transcriptional transactivation domain. Inhibition of ERK5 has therapeutic potential in cancer and inflammation and this has prompted the development of ERK5 kinase inhibitors (ERK5i). However, few ERK5i programmes have taken account of the ERK5 transactivation domain. We have recently shown that the binding of small molecule ERK5i to the ERK5 kinase domain stimulates nuclear localisation and paradoxical activation of its transactivation domain. Other kinase inhibitors paradoxically activate their intended kinase target, in some cases leading to severe physiological consequences highlighting the importance of mitigating these effects. Here, we review the assays used to monitor ERK5 activities (kinase and transcriptional) in cells, the challenges faced in development of small molecule inhibitors to the ERK5 pathway, and classify the molecular mechanisms of paradoxical activation of protein kinases by kinase inhibitors

Genes required for free phage production are essential for pseudomonas aeruginosa chronic lung infections

The opportunistic pathogen Pseudomonas aeruginosa causes chronic lung infection in patients with cystic fibrosis. The Liverpool Epidemic Strain LESB58 is highly resistant to antibiotics, transmissible, and associated with increased morbidity and mortality. Its genome contains 6 prophages and 5 genomic islands. We constructed a polymerase chain reaction (PCR)-based signature-tagged mutagenesis library of 9216 LESB58 mutants and screened the mutants in a rat model of chronic lung infection. A total of 162 mutants were identified as defective for in vivo maintenance, with 11 signature-tagged mutagenesis mutants having insertions in prophage and genomic island genes. Many of these mutants showed both diminished virulence and reduced phage production. Transcription profiling by quantitative PCR and RNA-Seq suggested that disruption of these prophages had a widespread trans-acting effect on the transcriptome. This study demonstrates that temperate phages play a pivotal role in the establishment of infection through modulation of bacterial host gene expression

Hidden Hunger: Solutions for America’s Aging Populations

The global population, including the United States, is experiencing a demographic shift with the proportion of older adults (aged ≥ 65 years) growing faster than any other age group. This demographic group is at higher risk for developing nutrition-related chronic conditions such as heart disease and diabetes as well as infections such as influenza and pneumonia. As a result, an emphasis on nutrition is instrumental for disease risk reduction. Unfortunately, inadequate nutrient status or deficiency, often termed hidden hunger, disproportionately affects older adults because of systematic healthcare, environmental, and biological challenges. This report summarizes the unique nutrition challenges facing the aging population and identifies strategies, interventions, and policies to address hidden hunger among the older adults, discussed at the scientific symposium “Hidden Hunger: Solutions for America’s Aging Population”, on March 23, 2018

Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations

Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.</p

Hidden Hunger:Solutions for America's Aging Populations

The global population, including the United States, is experiencing a demographic shift with the proportion of older adults (aged 65 years) growing faster than any other age group. This demographic group is at higher risk for developing nutrition-related chronic conditions such as heart disease and diabetes as well as infections such as influenza and pneumonia. As a result, an emphasis on nutrition is instrumental for disease risk reduction. Unfortunately, inadequate nutrient status or deficiency, often termed hidden hunger, disproportionately affects older adults because of systematic healthcare, environmental, and biological challenges. This report summarizes the unique nutrition challenges facing the aging population and identifies strategies, interventions, and policies to address hidden hunger among the older adults, discussed at the scientific symposium Hidden Hunger: Solutions for America's Aging Population, on March 23, 2018