4 research outputs found
Difluoro-dioxolo-benzoimidazol-benzamides As Potent Inhibitors of CK1δ and ε with Nanomolar Inhibitory Activity on Cancer Cell Proliferation
Deregulation
of CK1 (casein kinase 1) activity can be involved
in the development of several pathological disorders and diseases
such as cancer. Therefore, research interest in identifying potent
CK1-specific inhibitors is still increasing. A previously published
potent and selective benzimidazole-derived CK1δ/ε-specific
inhibitor compound with significant effects on several tumor cell
lines was further modified to difluoro-dioxolo-benzoimidazole derivatives
displaying remarkable inhibitory effects and increased intracellular
availability. In the present study, we identified two heterocyclic
molecules as new CK1-specific inhibitor compounds with favorable physicochemical
properties and notable selectivity in a kinome-wide screen. Being
compared to other CK1 isoforms, these compounds exhibited advanced
isoform selectivity toward CK1δ. Moreover, newly designed compounds
showed increased growth inhibitory activity in a panel of different
tumor cell lines as determined by analyses of cell viability and cell
cycle distribution. In summary, presented lead optimization resulted
in new highly selective CK1δ-specific small molecule inhibitors
with increased biological activity
Empagliflozin in Patients with Chronic Kidney Disease
Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo