GLPG0974 / Lakefront Biotherapeutics - LARVOL DELTA

Late Breaking Abstract - Butyrate attenuates airway remodeling and shifts macrophage polarization toward an IL-10-associated M2 phenotype via GPR43 receptor signalling in murine COPD. (ERS 2026) - "CS exposure increased inflammatory cell populations and inflammatory mediators in BALF, except for IL-10. CS also increased mucus secretion and collagen deposition, disrupted elastic fibres, upregulated M1 macrophage populations, and reduced M2 macrophage populations. Butyrate attenuated lung inflammation, inflammatory mediator secretion, airway remodeling, and M1 macrophage accumulation."

Late-breaking abstract • Preclinical • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pneumonia • Respiratory Diseases • CCL2 • CCL3 • CD163 • CD80 • CXCL1 • IL10 • IL1B • IL6 • ITGAM • MRC1 • TGFB1 • TNFA

Yunpi Xiaoji Formula Restores Gut-Brain Axis Homeostasis in Infantile Anorexia by Targeting the SCFAs-GPR43 Signaling Pathway. (PubMed, J Ethnopharmacol) - "YPXJF ameliorates IA by modulating the SCFAs-GPR43 pathway and restores gut-brain axis homeostasis by attenuating pathological anorexigenic signaling and restoring physiological appetite regulation. This study provides a mechanistic basis for YPXJF's clinical application and identifies GPR43 as a promising therapeutic target."

Journal • Anorexia

Universal pipeline for high-resolution GPCR structure determination. (PubMed, Nat Struct Mol Biol) - "NOAH enabled structure determination of vasopressin V2 receptor bound to the antagonist tolvaptan or partial agonist OPC51803 and bradykinin B2 receptor bound to the antagonist icatibant, revealing receptor activation and inhibition mechanisms. Coupling NOAH to ARK1 improved the V2 receptor-tolvaptan map and enabled high-resolution structures of lysophosphatidic acid receptor 2 bound to Ki16425 and free fatty acid receptor 2 bound to GLPG0974. NOAH-ARK1 minimizes trial-and-error construct optimization and provides a broadly applicable route for GPCR structural analysis and drug discovery."

Journal • AURKA

Acetate ameliorates membranous nephropathy by modulating the immune response and podocyte function. (PubMed, BMC Nephrol) - "Acetate ameliorates experimental MN through coordinated immunomodulatory effects and amelioration of podocyte foot process effacement. These findings support targeting acetate pathways as a mechanistically plausible adjunct strategy with low potential toxicity for MN."

Journal • Glomerulonephritis • Nephrology • Renal Disease • CD4 • WT1

Ameliorative effect of Polygonatum cyrtonema Hua polysaccharide on HFD/STZ-induced type 2 diabetes mice via improving gut microbiota imbalance and glucose metabolism disorder. (PubMed, Int J Biol Macromol) - "Further validation using NCI-H716 cells treated with the inhibitor GLPG0974 demonstrated that GLP-1 and PYY secretion were indirectly promoted by SCFAs through activating GPR43 receptor, but not entirely dependent on GPR43 pathway. In conclusion, this study indicated that PCP1 ameliorated T2DM probably through improving gut microbiota imbalance and glucose metabolism disorder, thereby establishing a theoretical foundation for the prebiotic development of P. cyrtonema Hua a polysaccharide."

Journal • Preclinical • Diabetes • Hepatology • Inflammation • Liver Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Gut microbiota-mediated short-chain fatty acids contribute to the protective effects of Xiaoxuming decoction against lipopolysaccharide-induced acute lung injury. (PubMed, J Tradit Chin Med) - "XXMD's therapeutic effect may be related to gut microbiota-mediated SCFAs, which alleviated LPS-induced ALI."

Journal • Acute Lung Injury • Oncology • Respiratory Diseases • IL1B • IL6 • NFKB1 • OCLN • TJP1 • TNFA

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