GLPG0974 / Galapagos - LARVOL DELTA

Liqi Yangyin formula ameliorates CUMS-induced depression and comorbid constipation via ACE/FFAR2 modulation of the microbiota-gut-brain axis. (PubMed, Front Cell Infect Microbiol) - "In vitro studies confirmed that ACE suppresses microglial inflammation through upregulating FFAR2 expression, an effect that was attenuated by the FFAR2 inhibitor GLPG0974. These findings suggest that LQYY modulates the gut-brain axis through ACE/FFAR2, offering a promising therapeutic approach for depression and constipation."

Journal • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Inflammation • Mood Disorders • Psychiatry

Lactiplantibacillus plantarum BD7807 ameliorates high-fat diet-induced lipid metabolic disorders and intestinal dysfunction via SCFAs-GPR43 pathway. (PubMed, Food Res Int) - "Further validation using the GPR43 inhibitor GLPG0974 confirmed that the protective effects of strain BD7807 on lipid metabolism and intestinal barrier function were partially dependent on the SCFAs-GPR43 signaling axis. Overall, L. plantarum BD7807 has the potential to ameliorate HFD-induced metabolic disorders."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • CD36 • FASN • HDAC3 • MUC2 • SCARB1

Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2. (PubMed, Nat Commun) - "Moreover, our structures reveal that GLPG0974 functions as an allosteric antagonist by binding adjacent to the orthosteric pocket to block agonist binding, whereas 4-CMTB binds the outer surface of transmembrane helices 6 and 7 to directly activate the receptor. Supported by computational and functional studies, these insights illuminate diverse mechanisms of ligand action, paving the way for precise GPCR-targeted drug design."

Journal

Regulation of Bifidobacterium-short chain fatty acid metabolism and improvement of intestinal toxicity of vinegar-processed Euphorbiae Pekinensis Radix (PubMed, Zhongguo Zhong Yao Za Zhi) - "The use of the free fatty acid receptor-2 inhibitor GLPG0974 verified that this improvement effect was related to the SCFAs pathway. This study demonstrates that Bifidobacterium is the key microbial community responsible for reducing intestinal toxicity in vinegar-processed Euphorbiae Pekinensis Radix. Vinegar-processing increases the abundance of Bifidobacterium, elevates the intestinal SCFAs content, inhibits intestinal inflammation, and enhances the expression of tight junction proteins, thereby improving the intestinal toxicity of Euphorbiae Pekinensis Radix."

Journal • Inflammation • Inflammatory Bowel Disease • Transplantation

Melatonin treatment increases skin microbiota-derived propionic acid to alleviate atopic dermatitis. (PubMed, J Allergy Clin Immunol) - "Our study demonstrates that melatonin alleviates AD through skin microbiota/propionic acid/GPR43/FABP5 axis, highlighting a novel role of melatonin as a modulator of skin microbiota to alleviate AD."

Journal • Atopic Dermatitis • CNS Disorders • Dermatitis • Dermatology • Immunology • Sleep Disorder • Transplantation • FABP5

Protective effect of microbiota-derived short chain fatty acids on vascular dysfunction in mice with systemic lupus erythematosus induced by toll like receptor 7 activation. (PubMed, Pharmacol Res) - "Our objective was to investigate whether short-chain fatty acids (SCFAs), specifically acetate and butyrate, could prevent vascular dysfunction and elevated blood pressure (BP) in mice with systemic lupus erythematosus (SLE) induced by TLR7 activation using imiquimod (IMQ)...Notably, the effects attributed to acetate, but not butyrate, were nullified when co-administered with the GPR43 antagonist GLPG-0974...These effects were counteracted in GF mice through treatment with either acetate or butyrate. To conclude, these findings underscore the potential of SCFA consumption in averting hypertension by restoring balance to the interplay between the gut, immune system, and vascular wall in SLE induced by TLR7 activation."

Journal • Preclinical • Cardiovascular • Hypertension • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

Houpo Paiqi Mixture Promotes Intestinal Motility in Constipated Rats by Modulating Gut Microbiota and Activating 5-HT-cAMP-PKA Signal Pathway. (PubMed, J Appl Microbiol) - "HPPQM manifested a curative effect in constipated rats by promoting intestinal motility. The underlying mechanisms might be related to modulating gut microbiota and activating 5-HT-cAMP-PKA signal pathway."

Journal • Preclinical • Constipation • Gastroenterology • Gastrointestinal Disorder

Acetate suppresses myocardial contraction via the short-chain fatty acid receptor GPR43. (PubMed, Front Physiol) - "Furthermore, the GPR43 antagonist GLPG0974 prevented the acetate-induced inhibitory effect on myocardial contraction. We conclude that acetate transiently inhibits contraction via the short-chain fatty acid receptor GPR43 in cardiomyocytes."

Journal • Cardiovascular

Constitutively active GPR43 is crucial for proper leukocyte differentiation. (PubMed, FASEB J) - "Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity...However, the activity of GPR43 did not contribute to butyrate-induced apoptosis in differentiated HL-60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes."

Journal • Hematological Malignancies • Leukemia • Oncology

Leuconostoc mesenteroides utilizes glucose fermentation to produce electricity and ameliorates high-fat diet-induced abdominal fat mass. (PubMed, Arch Microbiol) - "The level of 4-HNE and abdominal fat depot were markedly increased in mice administered with cyclophilin A inhibitor-pretreated bacteria or GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Our studies suggest a novel means by which the probiotic bacteria can modulate fat mass deposition and oxidative stress via the cyclophilin A-mediated electron production and the butyric acid-activated Ffar2 pathway."

Journal

Short Chain Fatty Acids Protect the Cognitive Function of Sepsis Associated Encephalopathy Mice via GPR43. (PubMed, Front Neurol) - "A total of 55 male adult C57BL/6 mice (2-3 months of age, 20-25 g) were divided into four groups randomly: sham group (n = 10), cecal ligation and puncture group (CLP group, n = 15), CLP+SCFAs group (n = 15), and CLP+SCFAs+GLPG0974 group (n = 15)...Our study suggested that in SAE, the levels of acetate and propionate decreased significantly, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFAs-producing bacteria. GPR43 was essential for the anti-neuroinflammation and cognitive protective effect of SCFAs in SAE."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Septic Shock • IL1B • IL6 • TNFA

Allosteric receptor modulation uncovers an FFA2R antagonist as a positive orthosteric modulator/agonist in disguise. (PubMed, Cell Signal) - "In the presence of GLPG0974, the response of neutrophils induced by the co-agonistic PAMs included an increase in the cytosolic concentration of free calcium ions (Ca), and this effect was reciprocal in that GLPG0974 triggered an increase in intracellular Ca, demonstrating that GLPG0974 acted as an FFA2R agonist. In summary, by studying the effects of the FFA2R ligand GLPG0974 on neutrophil activation induced by the co-agonists AZ1729 + Cmp58, we show that GLPG0974 is not only an FFA2R antagonist, but also displays agonistic and positive FFA2R-modulating functions that affect NADPH-oxidase activity and alter the receptor-downstream signaling induced by the co-agonistic PAMs."

Journal • Immunology • Inflammation

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis. (PubMed, Molecules) - "Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • MPO

Gut probiotic Lactobacillus rhamnosus attenuates PDE4B-mediated interleukin-6 induced by SARS-CoV-2 membrane glycoprotein. (PubMed, J Nutr Biochem) - "The probiotic activity of L. rhamnosus plus mycelia against membrane glycoprotein was abolished in mice treated with GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Activation of Ffar2 in the gut-lung axis for down-regulation of the PDE4B-IL-6 signalling may provide targets for development of modalities including probiotics for treatment of the cytokine storm in COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • IL6

Degradation products of azetidine core G334089 - Isolation, structure elucidation and pathway. (PubMed, J Pharm Biomed Anal) - "An extensive forced degradation study using hydrolytic degradation conditions was performed on G334089, the S-enantiomer of the free fatty acid receptor 2 (FFA2) antagonist GLPG0974, to identify the degradation product structures and discern degradation pathways...The determined structures, retention times and fragmentation patterns were used to identify the original degradation products and postulate a degradation pathway. In addition to the expected amide bond hydrolysis, a second degradation mechanism involving azetidine activation through formation of an azetidinium ion was demonstrated."

Journal

[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020) - "Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development."

Hematological Malignancies • Leukemia • Oncology • CD34 • MLL

[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020) - "Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development."

Hematological Malignancies • Leukemia • Oncology • CD34 • MLL

[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020) - "Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development."

Hematological Malignancies • Leukemia • Oncology • CD34 • MLL

[VIRTUAL] Only embryonic hematopoietic stem cells from umbilical cord blood can be brought to malignant progression by MLL-AF4 translocations (DGHO 2020) - "Proliferation and the impact of FFAR2 antagonist GLPG0974 were determined by Trypan blue staining... In summary, our study highlights the feasibility of engineering chromosomal translocations at their endogenous loci in human HSPCs derived from both huCB and huBM to generate pure MLLr cells as innovative and authentic human leukemia model. Further, we show that MLL-AF4 is unable to transform HSPCs derived from huBM cells indicating an important role of the fusion partner and the cell of origin. Mechanistically, downregulation of FFAR2 seems to be mandatory for leukemia development."

Hematological Malignancies • Leukemia • Oncology • CD34 • MLL

Mouse Abdominal Fat Depots Reduced by Butyric Acid-Producing Leuconostoc mesenteroides. (PubMed, Microorganisms) - "The inhibition of free fatty acid receptor 2 (Ffar2) by its antagonist, GLPG-0974, markedly diminished the probiotic effects of L. mesenteroides EH-1 plus glucose on the suppression of HFD-induced PPAR-γ and abdominal fats. Besides demonstrating the probiotic value of L. mesenteroides EH-1, our results highlight the possible therapy targeting the butyric acid-activated Ffar2 pathway to reduce abdominal fats."

Journal • Preclinical

Exercise Ameliorates Insulin Resistance of Type 2 Diabetes through Motivating Short-Chain Fatty Acid-Mediated Skeletal Muscle Cell Autophagy. (PubMed, Biology (Basel)) - "However, the administration of GLPG0974-the inhibitor of G protein-coupled receptor 43 (GPR43), which is the receptor of SCFAs-abolished exercise-mediated alleviation in IR in vivo and acetate-mediated reduction of skeletal muscle IR (SMIR) in vitro... Exercise-mediated SCFAs-upregulation may ameliorate insulin resistance (IR) through increasing autophagy of skeletal muscle cells by binding to GPR43. This study provides a theoretical basis for targeting gut bacterial metabolites to prevent T2DM."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Oncoprotective Effects of Short-Chain Fatty Acids on Uterine Cervical Neoplasia. (PubMed, Nutr Cancer) - "We also found that SCFAs inhibited the proliferation of HeLa cells, and a FFAR2 antagonist, GLPG0974, used to suppress the binding of SCFAs significantly restored the cell viability of HeLa cells blocked by acetic acid treatment. These results suggest that ingestion of prebiotics and the resulting production of SCFAs may play an oncoprotective role against uterine cervical neoplasia via FFAR2 expression."

Journal • Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor

Charles River Laboratories to acquire Galapagos’ Argenta and BioFocus service operations for up to €134 million (Galapagos Press Release) - "Galapagos NV...announces the signing of a definitive agreement to sell the BioFocus and Argenta service division operations to Charles River Laboratories International, Inc...for a total consideration of up to €134 million. The transaction is subject to customary closing conditions and is expected to close early in the second quarter of 2014."; Proceeds will be used for Galapagos’ pipeline progress.

Anticipated M & A • Financing • Immunology • Inflammatory Bowel Disease • Psoriasis • Rheumatoid Arthritis

Galapagos reports 2013 financial results (Galapagos Press Release) - P2, N=595; DARWIN1 (NCT01888874); Sponsor: Galapagos; Anticipated topline 12 week P2b data with GLPG0634 in RA in H2 2014; P2, N=64; NCT01782664; Sponsor: GlaxoSmithKline; P2, N=45; NCT01829321; Sponsor: Galapagos; Anticipated P2 data from GSK2586184 for psoriasis and GLPG0974 data in ulcerative colitis in H1 2014; "The Company expects to make significant progress in both partnered and non-partnered R&D programs as the pipeline continues to mature across a broad range of therapeutic  areas, resulting in multiple additional clinical and pre-clinical stage programs by end 2014."

Anticipated P2 data • Pipeline update • Immunology • Inflammatory Bowel Disease • Psoriasis • Rheumatoid Arthritis

The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs. (PubMed, Front Pharmacol) - "...HUVEC were pre-incubated with acetate, butyrate or propionate alone or in combination with GLPG0974 (GLPG, antagonist of GPR43) or β-hydroxybutyrate (SHB, antagonist of GPR41) and then exposed to LPS or TNFα...Furthermore, inhibition of HDACs mediates the effects of butyrate and propionate on IL-8 production, VCAM-1 expression, and PBMC adhesion to an endothelial monolayer. These data indicate the beneficial roles of SCFA in preventing vascular inflammation and relevant diseases by activation of GPR41/43 and inhibition of HDACs."

Journal • Atherosclerosis • Biosimilar • Cardiovascular • Dyslipidemia • Immunology