A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia

Olson, Eric J.; Mahar, Kelly M.; Haws, Thomas F.; Fossler, Michael J.; Gao, Feng; Gouville, Anne-Charlotte de; Sprecher, Dennis L.; Lepore, John J.

doi:10.1002/cpdd.704

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…lowered circulating free fatty acids, they did not deliver the expected niacin-like effects on circulating lipoproteins in patients 4 . Subsequently, this lack of effect on lipoprotein levels was also reported for GSK256073 37 . Thus, although this eliminated HCAR2/GPR109A as a drug target for the treatment of dyslipidemia, HCAR2 agonists do inhibit lipolysis, which potentially could be beneficial in e.g.…”

Section: Hcar2 As a Drug Target – From Dyslipidemia And Diabetes To I...mentioning

confidence: 72%

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Shenol,

Tenente,

Lückmann

et al. 2024

Nat Commun

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A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.

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Section: Hcar2 As a Drug Target – From Dyslipidemia And Diabetes To I...mentioning

confidence: 72%

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Shenol,

Tenente,

Lückmann

et al. 2024

Nat Commun

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“… 43 Another GPR109A agonist that did not exert anti-dyslipidemia effect in clinical studies, GSK256073, should be assessed for antipsychotic activity as well. 67 …”

Section: Conclusion and Future Researchmentioning

confidence: 99%

Anthranilic Acid, a GPR109A Agonist, and Schizophrenia

Oxenkrug,

Forester

2024

Int J�Tryptophan�Res

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Introduction: Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia. Data: Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment ( r = .625, P < .019, Spearman’s test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (−.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets). Discussion: Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.

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“…Based on the above, GPR109A agonists can be used for cancer prevention, 137 such as β-hydroxybutyrate and dietary fiber. Meanwhile, synthetic GPR109A-specific agonists MK1903, 141 acifran, 142 5-aminonicotinic acid (5-ANA), 143 GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) 144 has been explored for its role in vascular and inflammatory diseases, but no preclinical and clinical studies have demonstrated their effectiveness in tumors. To find a strong targeting GPR109A agonist will provide a huge potential in tumor therapy.…”

Section: Metabolite Sensing and Epigenetic Regulation Of Fatty Acid M...mentioning

confidence: 99%

Signaling pathways in cancer metabolism: mechanisms and therapeutic targets

You

Xie

Zhang

et al. 2023

Sig Transduct Target Ther

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A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.

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A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia

Cited by 9 publications

References 29 publications

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode

Anthranilic Acid, a GPR109A Agonist, and Schizophrenia

Signaling pathways in cancer metabolism: mechanisms and therapeutic targets

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