Undisclosed GPR174 inhibitor / Omeros - LARVOL DELTA

Analysis of transcription profiles for the identification of master regulators as the key players in glioblastoma. (PubMed, Comput Struct Biotechnol J) - "The role of some of them in GBM is not currently investigated: lysophosphatidic acid receptors 5 and 6, sphingosine-1-phosphate receptor 4, lysophosphatidylserine receptors GPR34 and GPR174, and G protein-coupled receptors 84 and 132 for fatty acids. Information on the revealed MRs can be used to search for novel therapeutic strategies to treat GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Interactions between gut microbes and host promote degradation of various fiber components in Meishan pigs. (PubMed, mSystems) - "In LW, microbial profiles along with GPR183 and GPR174 exhibited negative correlations with butyrate and propionate, respectively...By integrating multi-omics data, we constructed a framework outlining host-microbiota interactions that control dietary fiber utilization in pigs. Our data provide novel insights into host-microbiota interactions regulating fiber degradation and lay some theoretical foundations for improving the utilization efficiency of high-fiber cereal feed in pigs through targeted modulation of gut microbial function."

Journal • GPR183 • SLC2A4

Insights into lysophosphatidylserine recognition and Gα12/13-coupling specificity of P2Y10. (PubMed, Cell Chem Biol) - "This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα13 engagement of P2Y10 and identifies key determinants for Gα12-vs.-Gα13-coupling selectivity, whose mutations selectively disrupt Gα12 engagement while preserving the intact coupling of Gα13. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα12/13 coupling specificity."

Journal • Immunology

Combined high-resolution H3K27ac epigenomic and single-cell transcriptional profiling as a signature predictive of response to neoadjuvant immune checkpoint inhibitors (ICI) in urothelial cancer (UC). (ASCO 2024) - "When translated to a gene expression signature, we found enhancers at novel and known genes described in UC that included CYTOR, TGFBR2 and IKZF1(involved in immunotherapy response) and FYN, PDE4B and GPR174 involved in cell migration, microenvironment and EMT among the top ten genes... Our combined epigenetic and scRNAseq strategy revealed the existence of specific microenvironment and tumor states in pre-treatment samples from MIBC. We also provided a novel gene signature predictive of response. Prospective validation is ongoing."

Checkpoint inhibition • Clinical • IO biomarker • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CYTOR • IKZF1 • TGFBR2 • TMB

Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174. (PubMed, PLoS Biol) - "By structural comparison, we identified the structural features of GPR34 and GPR174 in active state. Taken together, our findings provide insights into ligand recognition and signaling of LysoPS receptors and will facilitate the development of novel therapeutics for related inflammatory diseases and autoimmune diseases."

Journal • Immunology • Inflammation

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive G signaling. (PubMed, Nat Commun) - "The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands."

Journal

Antibiotic Treatment During Infancy Alters the Gut Microbiome and Metabolites in Conjunction With the Lung Transcriptome (ATS 2023) - "Newborns (males=5, females=5) received a daily dose of a broad-spectrum antibiotic cocktail consisting of ampicillin, gentamicin, and vancomycin (targeting both gram positive and negative bacteria) for 7 days during the first week of life; control animals received saline (males=3, females=5)...In addition, antibiotic-treated males showed dysregulation of lung GPR expression for P2RY14, SUCNR1, GPR174, and LPAR5 relative to controls. Antibiotic-treated infant monkeys showed significant differences in pathways known to produce short-chain fatty acids, with evidence of sex-dependent effects in Mixed Acid Fermentation pathways. The presence of GPRs in the lung that can respond to microbial metabolites suggests a potential mechanism by which alterations in the gut microbiome following early-life antibiotic treatment may influence normal lung development."

Infectious Disease • Respiratory Diseases • LPAR5 • P2RY14 • SUCNR1

Exploration of LPS agonist binding modes using the combination of a new hydrophobic scaffold and homology modeling. (PubMed, Eur J Med Chem) - "Lysophosphatidylserine (LysoPS) is an endogenous pan-agonist of three G-protein coupled receptors (GPCRs): LPS/GPR34, LPS/P2Y, and LPS/GPR174, and we previously reported a series of LysoPS-based agonists of these receptors...The binding poses of LPS agonists to this site are consistent with easy incorporation of various kinds of fatty acid surrogates. Structural development based on this model afforded a series of potent and selective LPS full agonists, which showed enhanced in vitro actin stress fiber formation effect."

Journal

Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation. (PubMed, Nat Commun) - "Finally, the structure reveals a G engaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs."

Journal

Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains. (PubMed, Front Aging Neurosci) - "Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains...A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b. Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research."

Journal • Alzheimer's Disease • CNS Disorders

GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression. (PubMed, Nat Commun) - "Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases."

Journal • Preclinical • Cardiovascular • Peripheral Arterial Disease • AREG • EGR1

Activation of CCL21-GPR174/CCR7 on cardiac fibroblasts underlies myocardial ischemia/reperfusion injury. (PubMed, Front Genet) - " This study revealed several key factors underlying myocardial I/R injury. Of these, the activation of CCL21-GPR174/CCR7 signaling on cardiac fibroblasts was highlighted, which provides potential therapeutic targets for cardioprotection."

Journal • Cardiovascular • Myocardial Ischemia • Reperfusion Injury • CCL21 • CCR7 • CXCL13 • CXCR5 • EDN1

Lysophosphatidylserine may stimmulate liver fibrosis (EASL-ILC 2022) - "Lysophosphatidylserine (LysoPS), a phosphatidylserine-derived LPL, has recently been identified as a specific receptor, such as GPR34 and GPR174, P2Y10, and has begun to attract attention as a novel lipid mediator... In this study, it was suggested that LysoPS is involved in liver fibrosis in vitro. In vivo study, upregulation of LysoPS receptor was observed in hepatic myofibroblast-like stellate cells, suggesting that LysoPS may also be involved in liver fibrosis. Furthermore, an increase in LysoPS of some fatty acid molecular species was observed in mouse plasma, suggesting the possibility of laboratory medical application of LysoPS as a marker of liver fibrosis."

Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor • SMAD3

Germinal Center-Related G Protein-Coupled Receptors in Antibody-Mediated Autoimmune Skin Diseases: from Basic Research to Clinical Trials. (PubMed, Clin Rev Allergy Immunol) - "This review will give an introduction on the ligands and functions of two types of GC-relating GPCRs-chemokine receptors like CXCR4 and CXCR5, as well as emerging de-orphanized GPCRs like GPR183, GPR174, and P2RY8...Besides, GPCRs are excellent drug targets due to the unique structure and vital functions. Therefore, this review is aimed at providing readers with a focused knowledge about the role that GPCRs play in GC reaction, as well as in provoking the development of GPCR-targeting agents for immune-mediated diseases besides autoimmune diseases."

Journal • Review • Dermatology • Dermatomyositis • Fibrosis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Scleroderma • Systemic Lupus Erythematosus • Systemic Sclerosis • CXCR4 • CXCR5 • GPR183 • P2RY8

Gpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells. (PubMed, Front Immunol) - "Our study indicated that GPR174 was involved in the pathogenesis of IBD by regulating the maturation of the dendritic cells to maintain immune homeostasis. TNF-α (NF-κB) signaling pathway, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways may be the target pathway."

IO biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • CD40 • CD86 • IFNG • IL10 • IL4 • IL6 • TNFA

GPR174 signals via Gαs to control a CD86-containing gene expression program in B cells. (PubMed, Proc Natl Acad Sci U S A) - "Variants in the GPR174 locus have been associated with autoimmune diseases. Our findings provide knowledge for understanding how alterations in GPR174 expression may contribute to disease."

Journal • Immunology • CD86

Gene Expression Risk Profiles and Interstitial Lung Abnormalities (ATS 2022) - "We developed an ILA score using penalized regression with 11 of 50 genes (BTN3A1*, CPED1*, CXCR6, GBP4*, GPR174*, IL7R, LBH, LPAR6*, LRRC39, NAP1L2*, PLBD1) from the IPF score selected; 6 of these transcripts (*) had discordant directions of effects compared to the IPF score... Genes predicting higher risk of IPF mortality are also associated with risk to developing ILA and partially mediate the effects of aging on mortality. These results suggest shared biology, including immunoregulatory and Butyrophilin interactions, along the spectrum of the development of ILA, progression of IPF, and the relationship of aging to death from all causes."

Chronic Obstructive Pulmonary Disease • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • BTN3A1 • CXCR6 • IL7R