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.

Stomach content and stable isotope analyses provide complementary insights into the trophic ecology of coastal temperate bentho-demersal assemblages under environmental and anthropogenic pressures.

Assessing organic matter fluxes and species interactions in food webs is of main interest to understand the ecological functioning in bays and estuaries characterised by a wide diversity of primary producers and consumers. Demersal fish and cephalopod assemblages were studied across a network of 24 shallow subtidal stations in the bay of Saint-Brieuc for their diversity, stable isotope compositions and stomach contents. The community was composed of 21 taxa, eight species accounting for 94.

Spatio-temporal patterns in stable isotope composition of a benthic intertidal food web reveal limited influence from salt marsh vegetation and green tide.

Assessing fluxes of matter and energy in food webs within and across benthic habitats is important to understand the ecological functioning in bays and estuaries, where the productivity is favoured by a wide diversity of primary producers. The temporal variability (March vs September 2019) in the carbon and nitrogen stable isotope composition of primary food sources and benthic invertebrates consumers was investigated in a large intertidal area (Western English-Channel, France). The study area is influenced by megatidal conditions and characterised by salt marshes in the sheltered part, and seasonal Ulva spp.