Characterization of GLPG1205 in Mouse Fibrosis Models: A Potent and Selective Antagonist of GPR84 for Treatment of Idiopathic Pulmonary Fibrosis

Sanière, Laurent; Marsais, Florence; Jagerschmidt, Catherine; Meurisse, S.; Čužić, Snježana; Shoji, Kenji F.; Clément-Lacroix, P.; Osselaer, Nancy Van; Vos, Steve De

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a1046

Cited by 12 publications

(16 citation statements)

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“…This drug reduced experimental kidney as well as liver fibrosis and was found to block hepatic stellate cell activation via modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway [14,43]. Moreover, GLPG1205, a nanomolar potency GPR84 antagonist, has demonstrated reduced lung fibrosis in two mouse models in a therapeutic setting [44]. Our study highlights the beneficial effects of small molecule GPR84 antagonists in experimental models of liver injury, steatohepatitis and fibrosis.…”

Section: Discussionmentioning

confidence: 62%

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

Puengel

Vos

Hundertmark

et al. 2020

JCM

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Medium-chain fatty acids (MCFAs) have been associated with anti-steatotic effects in hepatocytes. Expression of the MCFA receptor GPR84 (G protein-coupled receptor 84) is induced in immune cells under inflammatory conditions and can promote fibrogenesis. We aimed at deciphering the role of GPR84 in the pathogenesis of non-alcoholic steatohepatitis (NASH), exploring its potential as a therapeutic target. GPR84 expression is upregulated in liver from patients with non-alcoholic fatty liver disease (NAFLD), correlating with the histological degree of inflammation and fibrosis. In mouse and human, activated monocytes and neutrophils upregulate GPR84 expression. Chemotaxis of these myeloid cells by GPR84 stimulation is inhibited by two novel, small molecule GPR84 antagonists. Upon acute liver injury in mice, treatment with GPR84 antagonists significantly reduced the hepatic recruitment of neutrophils, monocytes, and monocyte-derived macrophages (MoMF). We, therefore, evaluated the therapeutic inhibition of GPR84 by these two novel antagonists in comparison to selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, in three NASH mouse models. Pharmacological inhibition of GPR84 significantly reduced macrophage accumulation and ameliorated inflammation and fibrosis, to an extent similar to selonsertib. In conclusion, our findings support that GPR84 mediates myeloid cell infiltration in liver injury and is a promising therapeutic target in steatohepatitis and fibrosis.

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Section: Discussionmentioning

confidence: 62%

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

Puengel

Vos

Hundertmark

et al. 2020

JCM

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“…Mouse models of macrophage depletion would be a useful tool to explore this hypothesis further. A similar phenomenon may also occur in the lungs of idiopathic pulmonary fibrosis patients, where both infiltrating macrophages and bronchial epithelial cells express Gpr84 (Saniere et al, 2019). A recent study has also found Gpr84 is slightly upregulated in the lungs of rats with heart failure after myocardial infarction, and that expression in cultured human lung fibroblasts could be induced by transforming growth factor b and endothelin 1 (Nguyen et al, 2020).…”

Section: Molecular Inducermentioning

confidence: 68%

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

Luscombe

Lucy

Bataille

et al. 2020

DNA and Cell Biology

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GPR84 is an inflammation-induced receptor highly expressed on immune cells, yet its endogenous ligand is still unknown. This makes any interpretation of its physiological activity in vivo difficult. However, experiments with potent synthetic agonists have highlighted what the receptor can do, namely, enhance proinflammatory signaling and macrophage effector functions such as phagocytosis. Developing drugs to block these effects has attracted interest from the scientific community with the aim of decreasing disease activity in inflammatory disorders or enhancing inflammation resolution. In this review, we critically reassess the widely held belief that the major role of GPR84 is that of being a medium-chain fatty acid (MCFA) receptor. While MCFAs have been shown to activate GPR84, it remains to be demonstrated that they are present in relevant tissues at appropriate concentrations. In contrast to four other ''full-time'' free fatty acid receptor subtypes, GPR84 is not expressed by enteroendocrine cells and has limited expression in the gastrointestinal tract. Across multiple tissues and cell types, the highest expression levels of GPR84 are observed hours after exposure to an inflammatory stimulus. These factors obscure the relationship between ligand and receptor in the human body and do not support the exclusive physiological pairing of MCFAs with GPR84. To maximize the chances of developing efficacious drugs for inflammatory diseases, we must advance our understanding of GPR84 and what it does in vivo.

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“…In addition, initially, the single molecule DIM, and subsequently a substantial structure–activity analysis based on DIM, has defined a group of allosteric agonists. , However, although there is interest in the potential of agonists of GPR84 as therapeutic agents, ,, currently there is greater interest in the potential of antagonists of this receptor. , Despite this interest and potential opportunity, the only high affinity series of GPR84 antagonists described previously is exemplified by GLPG1205 . This ligand has been assessed clinically in both ulcerative colitis and in early studies in idiopathic pulmonary fibrosis . Although clinical efficacy end-points in ulcerative colitis were not achieved, the reported outcomes from the studies on idiopathic pulmonary fibrosis are encouraging (ClinicalTrials.gov Identifier: NCT03725852).…”

Section: Discussionmentioning

confidence: 99%

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84

Jenkins

Marsango

Mancini

et al. 2021

ACS Pharmacol. Transl. Sci.

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GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1H-indole as a high affinity and highly selective competitive antagonist of human GPR84. Tritiation of a di-iodinated form of the core structure produced [3H]3-((5,6-diphenyl-1,2,4-triazin-3-yl)methyl)-1H-indole, which allowed effective measurement of receptor levels in both transfected cell lines and lipopolysaccharide-treated THP-1 monocyte/macrophage cells. Although this compound series lacks significant affinity at mouse GPR84, homology modeling and molecular dynamics simulations provided a potential rationale for this difference, and alteration of two residues in mouse GPR84 to the equivalent amino acids in the human orthologue, predicted to open the antagonist binding pocket, validated this model. Sequence alignment of other species orthologues further predicted binding of the compounds as high affinity antagonists at macaque, pig, and dog GPR84 but not at the rat orthologue, and pharmacological experiments confirmed these predictions. These studies provide a new class of GPR84 antagonists that display species selectivity defined via receptor modeling and mutagenesis.

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Characterization of GLPG1205 in Mouse Fibrosis Models: A Potent and Selective Antagonist of GPR84 for Treatment of Idiopathic Pulmonary Fibrosis

Cited by 12 publications

References 0 publications

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84

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