Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC of 282.

Sediment grain size and benthic community structure in the eastern English Channel: Species-dependent responses and environmental influence.

This study addresses the scarcity of evidence on the relationship between benthic communities and coarse-grained sediments in the eastern English Channel. The region's geological history contributes to its predominantly coarse sediment composition. The study employs ternary plots to visualize benthic species' preferences and tolerance for sediment types, revealing their effectiveness.

Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.

Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound ), a potent and selective pan-SIK inhibitor (IC: 2.

Sediment migrations drive the dynamic of macrobenthic ecosystems in subtidal sandy bedforms.

A traditional taxonomic approach coupled to a biological traits analysis was conducted in order to provide a new insight into macrobenthic communities associated with subtidal sandy environments. Results suggest that the macro-scale distribution of benthic communities is mainly driven by the migration rate of bedforms (sandbank, barchan dune and transversal dune) which changes the sediment grain size and reduces macrobenthic diversity. A classic scheme of species/traits succession was also observed from less to more physically disturbed areas.

Renewable energy homes for marine life: Habitat potential of a tidal energy project for benthic megafauna.

An increasing number of offshore structures are being deployed worldwide to meet the growing demand for renewable energy. Besides energy production, these structures can also provide new artificial habitats to a diversity of fish and crustacean species. This study characterises how concrete mattresses that stabilise the submarine power cable of a tidal energy test site can increase habitat capacity for benthic megafauna.

Linking multiple facets of biodiversity and ecosystem functions in a coastal reef habitat.

Reef-building species play key roles in promoting local species richness and regulating ecosystem functions like biogeochemical fluxes. We evaluated the functioning of a habitat engineered by the reef-building polychaete Sabellaria alveolata, by measuring oxygen and nutrient fluxes in the reef structures and in the soft-sediments nearby. Then, we investigated the relative importance of temperature, the engineer S.

Long-term spatio-temporal changes of the muddy fine sand benthic community of the Bay of Seine (eastern English Channel).

In the English Channel, the eastern Bay of Seine is exposed to numerous anthropogenic disturbances, in particular major changes in sediment dynamics, which are expected to greatly impact benthic communities. To assess the long-term effects of these stressors on the muddy fine sand benthic community, an original long-term monitoring program has been implemented since 1988. It is based on the sampling of a network of 60 stations during seven surveys over 28 years from 1988 to 2016.

Impact of magnetic fields generated by AC/DC submarine power cables on the behavior of juvenile European lobster (Homarus gammarus).

The number of submarine power cables using either direct or alternating current is expected to increase drastically in coming decades. Data concerning the impact of magnetic fields generated by these cables on marine invertebrates are scarce. In this context, the aim of this study was to explore the potential impact of anthropogenic static and time-varying magnetic fields on the behavior of recently settled juvenile European lobsters (Homarus gammarus) using two different behavioral assays.

Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators.

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation.

Individual-based simulation of the spatial and temporal dynamics of macroinvertebrate functional groups provides insights into benthic community assembly mechanisms.

The complexity and scales of the processes that shape communities of marine benthic macroinvertebrates has limited our understanding of their assembly mechanisms and the potential to make projections of their spatial and temporal dynamics. Individual-based models can shed light on community assembly mechanisms, by allowing observed spatiotemporal patterns to emerge from first principles about the modeled organisms. Previous work in the Rance estuary (Brittany, France) revealed the principal functional components of its benthic macroinvertebrate communities and derived a set of functional relationships between them.

Latitudinal Patterns in European Seagrass Carbon Reserves: Influence of Seasonal Fluctuations versus Short-Term Stress and Disturbance Events.

Seagrass meadows form highly productive and valuable ecosystems in the marine environment. Throughout the year, seagrass meadows are exposed to abiotic and biotic variations linked to (i) seasonal fluctuations, (ii) short-term stress events such as, e.g.

Process-driven and biological characterisation and mapping of seabed habitats sensitive to trawling.

The increase of anthropogenic pressures on the marine environment together with the necessity of a sustainable management of marine living resources have underlined the need to map and model coastal environments, particularly for the purposes of spatial planning and for the implementation of integrated ecosystem-based management approach. The present study compares outputs of a process-driven benthic habitat sensitivity (PDS) model to the structure, composition and distribution of benthic invertebrates in the Eastern English Channel and southern part of the North Sea. Trawl disturbance indicators (TDI) computed from species biological traits and benthic community composition were produced from samples collected with a bottom trawl.

Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors.

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX-LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo[1,2-a]pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS).

Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis.

Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11).

Structural-functional studies of Burkholderia cenocepacia D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA) and characterization of inhibitors with antibiotic adjuvant and antivirulence properties.

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-β-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia.

From triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria.

In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.

Ephemeral bio-engineers or reef-building polychaetes: how stable are aggregations of the tube worm Lanice conchilega (Pallas, 1766)?

Dense aggregations of tube-worms can stabilize sediments and generate oases for benthic communities that are different and often more diverse and abundant than those of the surroundings. If these features are to qualify as biogenic reefs under nature-conservation legislation such as the EC Habitats Directive, a level of stability and longevity is desirable aside from physical and biological attributes. Lanice conchilega (Pallas, 1766) is widely distributed around the European coast and aggregations of this tube-dwelling polychaete are known to have a positive effect on the biodiversity of associated species in inter- and sub-tidal areas.

Towards Gram-negative antivirulence drugs: new inhibitors of HldE kinase.

Gram-negative bacteria lacking heptoses in their lipopolysaccharide (LPS) display attenuated virulence and increased sensitivity to human serum and to some antibiotics. Thus inhibition of bacterial heptose synthesis represents an attractive target for the development of new antibacterial agents. HldE is a bifunctional enzyme involved in the synthesis of bacterial heptoses.

Consequences of spring phytodetritus sedimentation on the benthic compartment along a depth gradient in the Eastern English Channel.

Phaeocystis blooms are of major importance in the Eastern English Channel, where they significantly contribute to spring organic matter input with chlorophyll concentrations commonly higher than 30 microgl(-1) in the water column. Post-bloom deposition of Phaeocystis derived mucilaginous compounds has been shown to have a major importance on benthic intertidal systems, but resulting mineralization processes and consequences on the macrobenthic compartment remain poorly documented in subtidal areas. In this frame, a study was performed along the French coast of the English Channel to quantify mineralization processes, as well as potential consequences on subtidal sediments, especially their geochemistry and associated macrofaunal communities.

Ruthenium-SYNPHOS-catalyzed asymmetric hydrogenations: an entry to highly stereoselective synthesis of the C15-C30 subunit of dolabelide A.

An efficient construction of the C15-C30 segment of the cytotoxic macrolide dolabelide A is described. The synthesis relies on ruthenium-SYNPHOS-mediated asymmetric hydrogenation reactions of beta-keto esters to generate the C19, C21, and C27 hydroxyl-bearing stereocenters with very high levels of enantio- and diastereoselectivity.

Does the Phaeocystis bloom affect the diel migration of the suprabenthos community?

The suprabenthos comprises all bottom-dependent animals, mainly crustaceans (including decapods and peracarids), which perform--with varying amplitude, intensity and regularity--seasonal or daily vertical migrations above the sea floor. The presence of organisms in the Benthic Boundary Layer is determined by two general factors: (1) organism behaviour, which depends on the light penetration in the water column and (2) boundary-layer hydrodynamics. In the coastal zone of the eastern English Channel, during the spring Phaeocystis bloom, the presence of gelatinous colonies modifies the penetration of light in the water column, which may seriously affect the abundance and/or the behaviour of the suprabenthos community.

The ecological quality status of the Bay of Seine and the Seine estuary: use of biotic indices.

Using recent indices developed, in part, for use under the European Water Framework Directive (AMBI, BENTIX, BOPA, BQI, I2EC and the trophic index ITI), the ecological quality status of two highly contaminated environments--the Bay of Seine and the Seine estuary (Eastern English Channel)--was determined on several spatial and temporal scales. Data from 604 observations gathered over a 14-year period (1988-2002) were analyzed, and the results used to show the relationship between biotic indices, environmental variables and classic descriptors (e.g.