GSK256073 / GSK - LARVOL DELTA

The hydroxycarboxylic acid receptor HCA2 is required for the protective effect of ketogenic diet in epilepsy. (PubMed, Pharmacol Res Perspect) - "Ketogenic diet is known to increase circulating levels of endogenous HCA2 agonists, and we show that the effect of ketogenic diet in reducing seizures in the 6 Hz seizure model is negated in HCA2-deficient mice. Our data support the potential of HCA2 as a target for the treatment of epilepsy and potentially for neurodegenerative diseases."

Journal • CNS Disorders • Epilepsy

Anthranilic Acid, a GPR109A Agonist, and Schizophrenia. (PubMed, Int J Tryptophan Res) - "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."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dyslipidemia • Metabolic Disorders • Psychiatry • Schizophrenia • KYNU

Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution. (PubMed, Nat Commun) - "Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor."

Journal • Dermatology • Dyslipidemia • Immunology • Metabolic Disorders • Psoriasis

Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2. (PubMed, Cell Rep) - "To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created...Additionally, conserved residues R111 and Y284, unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs."

Journal

Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2. (PubMed, Nat Commun) - "Here we report three cryo-EM structures of the human HCAR2-G signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation."

Journal • CNS Disorders • Dyslipidemia • Inflammation • Metabolic Disorders • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • MAGEE1

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. (PubMed, Clin Pharmacol Drug Dev) - "Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin-like lipid effects. These findings add to the increasing evidence that niacin-mediated lipoprotein changes occur predominantly via GPR109A-independent pathways."

Clinical • Journal • Dyslipidemia