Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics.

The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-ß inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.

Novel drug-like fluorenyl derivatives as selective butyrylcholinesterase and ß-amyloid inhibitors for the treatment of Alzheimer's disease.

Butyrylcholinesterase (BuChE) and amyloid ß (Aß) aggregation remain important biological target and mechanism in the search for effective treatment of Alzheimer's disease. Simultaneous inhibition thereof by the application of multifunctional agents may lead to improvement in terms of symptoms and causes of the disease. Here, we present the rational design, synthesis, biological evaluation and molecular modelling studies of novel series of fluorene-based BuChE and Aß inhibitors with drug-like characteristics and advantageous Central Nervous System Multiparameter Optimization scores. Among 17 synthesized and tested compounds, we identified 22 as the most potent eqBuChE inhibitor with IC50 of 38 nM and 37.4% of Aß aggregation inhibition at 10 µM. Based on molecular modelling studies, including molecular dynamics, we determined the binding mode of the compounds within BuChE and explained the differences in the activity of the two enantiomers of compound 22. A novel series of fluorenyl compounds meeting the drug-likeness criteria seems to be a promising starting point for further development as anti-Alzheimer agents.

Serotonin 5-HT6 Receptor Ligands and Butyrylcholinesterase Inhibitors Displaying Antioxidant Activity-Design, Synthesis and Biological Evaluation of Multifunctional Agents against Alzheimer's Disease.

Neurodegeneration leading to Alzheimer's disease results from a complex interplay of a variety of processes including misfolding and aggregation of amyloid beta and tau proteins, neuroinflammation or oxidative stress. Therefore, to address more than one of these, drug discovery programmes focus on the development of multifunctional ligands, preferably with disease-modifying and symptoms-reducing potential. Following this idea, herein we present the design and synthesis of multifunctional ligands and biological evaluation of their 5-HT6 receptor affinity (radioligand binding assay), cholinesterase inhibitory activity (spectroscopic Ellman's assay), antioxidant activity (ABTS assay) and metal-chelating properties, as well as a preliminary ADMET properties evaluation. Based on the results we selected compound 14 as a well-balanced and potent 5-HT6 receptor ligand (Ki = 22 nM) and human BuChE inhibitor (IC50 = 16 nM) with antioxidant potential expressed as a reduction of ABTS radicals by 35% (150 µM). The study also revealed additional metal-chelating properties of compounds 15 and 18. The presented compounds modulating Alzheimer's disease-related processes might be further developed as multifunctional ligands against the disease.

Risk and Benefit for Targeted Therapy Agents in Pediatric Phase II Trials in Oncology: A Systematic Review with a Meta-Analysis.

BACKGROUND: For research with human participants to be ethical, risk must be in a favorable balance with potential benefits. Little is known about the risk/benefit ratio for pediatric cancer phase II trials testing targeted therapies. OBJECTIVE: Our aim was to conduct a systematic review of preliminary efficacy and safety profiles of phase II targeted therapy clinical trials in pediatric oncology. METHODS: Our protocol was prospectively registered in PROSPERO (CRD42020146491). We searched EMBASE and PubMed for phase II pediatric cancer trials testing targeted agents. We included solid and hematological malignancy studies published between 1 January, 2015 and 27 February, 2020. We measured risk using drug-related grade 3 or higher adverse events, and benefit by response rates. When possible, data were meta-analyzed. All statistical tests were two-sided. RESULTS: We identified 34 clinical trials (1202 patients) that met our eligibility criteria. The pooled overall response rate was 24.4% (95% confidence interval [CI] 14.5-34.2) and was lower in solid tumors, 6.4% (95% CI 3.2-9.6), compared with hematological malignancies, 55.1% (95% CI 35.9-74.3); p < 0.001. The overall fatal drug-related (grade 5) adverse event rate was 1.6% (95% CI 0.6-2.5), and the average drug-related grade 3/4 adverse event rate per person was 0.66 (95% CI 0.55-0.78). CONCLUSIONS: We provide an estimate for the risks and benefits of participation in pediatric phase II cancer trials. These data may be used as an empirical basis for informed communication about benefits and burdens in pediatric oncology research.