title: Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?
abstract: The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda-G-protein-receptor-5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy.
authors.affiliation: Discovery Medicine, Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Hodge
authors.affiliation: Discovery Medicine, Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Nunez
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery / Q000639:trends; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D009928:Organ Specificity; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D057170:Translational Research, Biomedical / Q000639:trends
chemical_list: D019440:Anti-Obesity Agents; D015507:Drugs, Investigational; C473772:GPBAR1 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled
keywords: antidiabetic drug; antiobesity drug; drug development; experimental pharmacology