Large-Scale Modeling of Sparse Protein Kinase Activity Data.

Protein kinases are a protein family that plays an important role in several complex diseases such as cancer and cardiovascular and immunological diseases. Protein kinases have conserved ATP binding sites, which when targeted can lead to similar activities of inhibitors against different kinases. This can be exploited to create multitarget drugs. On the other hand, selectivity (lack of similar activities) is desirable in order to avoid toxicity issues. There is a vast amount of protein kinase activity data in the public domain, which can be used in many different ways. Multitask machine learning models are expected to excel for these kinds of data sets because they can learn from implicit correlations between tasks (in this case activities against a variety of kinases). However, multitask modeling of sparse data poses two major challenges: (i) creating a balanced train-test split without data leakage and (ii) handling missing data. In this work, we construct a protein kinase benchmark set composed of two balanced splits without data leakage, using random and dissimilarity-driven cluster-based mechanisms, respectively. This data set can be used for benchmarking and developing protein kinase activity prediction models. Overall, the performance on the dissimilarity-driven cluster-based split is lower than on random split-based sets for all models, indicating poor generalizability of models. Nevertheless, we show that multitask deep learning models, on this very sparse data set, outperform single-task deep learning and tree-based models. Finally, we demonstrate that data imputation does not improve the performance of (multitask) models on this benchmark set.

"Good Wine Makes Good Blood": An Integrated Approach to Characterize Autochthonous Apulian Grapevines as Promising Candidates for Healthy Wines.

Wine production represents an ancient human activity and one of the most economically important markets in Europe. Moreover, the health effects of grapes and related products have been largely demonstrated, and mostly depend on their richness in bioactive molecules such as flavonoid and non-flavonoid phenolic compounds. Italy has the highest global wine production and provides one of the richest grapevine germplasm in the Mediterranean area. In this paper, our attention was focused on the evaluation of the total phenol and anthocyanin content in five autochthonous Apulian grapevine cultivars, in both wines and their non-alcoholic extracts. Moreover, the potential antioxidant effects of the non-alcoholic wine extracts on the cell viability of Caco-2 and HeLa carcinoma cell lines were tested. Finally, for the most promising autochthonous selected cultivars (Negramaro, Nero di Troia and Susumaniello), comparative transcriptomic analysis in berries was performed using high-throughput sequencing technology.

Health-Nutrients and Origin Awareness: Implications for Regional Wine Market-Segmentation Strategies Using a Latent Analysis.

A healthy-nutrient wine has been recently developed by Apulian wineries (southern Italy), using autochthonous wine grapes cultivars, selected strains and specific processes of production. As such, this research elicits Italian wine consumers' preferences towards this innovative Apulian wine with regard to additional labelling information associated with health-nutrients and the origin of grapes on the bottle of wine. For this purpose, a social survey based on the choice experiment approach is considered. The results reveal a heterogeneity of preferences among respondents for which the origin of wine grapes cultivars is the most appreciated (an average Willingness-to-Pay of EUR 6.57), thereby inducing an increase in their function utility, while the health-nutrients attribute is relatively less appreciated (an average Willingness-to-Pay of EUR 3.95). Furthermore, four class consumers' cluster profile have been identified in respect to their: (i) behavior and propensity to wine consumption and purchase, (ii) health-claims importance on the wine bottle label, (iii) socio-economic characteristics and (iv) health conditions. This paper has marketing and public implications and contributes to an understanding of how additional information on the label of a wine bottle may affect the market-segmentation, influence wine consumers' utility, protect their health and increase their level of awareness to wine ingredients labelling.

Discovery and Optimization of Orally Bioavailable Phthalazone and Cinnolone Carboxylic Acid Derivatives as S1P2 Antagonists against Fibrotic Diseases.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.

Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.

MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.