Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?

Diabetes, Obesity and Metabolism

Volumn 18, Issue 5, 2016, Pages 439-443

  Hodge, R J ^a   Nunez, D J ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Antidiabetic drug; Antiobesity drug; Drug development; Experimental pharmacology

Indexed keywords

AGENTS AFFECTING METABOLISM; ANTIDIABETIC AGENT; BILE ACID; MEMBRANE RECEPTOR; PLACEBO; SB 756050; TAKEDA G PROTEIN RECEPTOR 5; TAKEDA G PROTEIN RECEPTOR 5 AGONIST; UNCLASSIFIED DRUG; ANTIOBESITY AGENT; G PROTEIN COUPLED RECEPTOR; GPBAR1 PROTEIN, HUMAN; NEW DRUG;

ARTICLE; COLITIS; DIET THERAPY; DNA METHYLATION; DOSAGE SCHEDULE COMPARISON; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; HUMAN; INTESTINE FLORA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; OUTCOME ASSESSMENT; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PRURITUS; RECEPTOR UPREGULATION; RISK BENEFIT ANALYSIS; SEX DIFFERENCE; AGONISTS; ANIMAL; ANTIBODY SPECIFICITY; BIOLOGICAL MODEL; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; DRUG DEVELOPMENT; METABOLISM; MOLECULARLY TARGETED THERAPY; OBESITY; PRECLINICAL STUDY; TRANSLATIONAL RESEARCH; TRENDS;

ANIMALS; ANTI-OBESITY AGENTS; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; DRUGS, INVESTIGATIONAL; HUMANS; HYPOGLYCEMIC AGENTS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; OBESITY; ORGAN SPECIFICITY; RECEPTORS, G-PROTEIN-COUPLED; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84960880692     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/dom.12636     Document Type: Article

References (43)

1. Kawamata Y, Fujii R, Hosoya M etal. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278: 9435-9440.
2. Maruyama T, Tanaka K, Suzuki J etal. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 2006; 191: 197-205.
3. Baptissart M, Vega A, Maqdasy S etal. Bile acids: from digestion to cancers. Biochimie 2013; 95: 504-517.
4. Schaap FG, Trauner M, Jansen PLM. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014; 11: 55-67.
5. Penney NC, Kinross J, Newton RC, Purkayasha S. The role of bile acids in reducing the metabolic complications of obesity after bariatric surgery: a systematic review. Int J Obes 2015; 39: 1565-1574.
6. Stepanov V, Stankov K, Mikov M. The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. J Recept Signal Transduct Res 2013; 33: 213-223.
7. Vassileva G, Golovko A, Markowitz L etal. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 2006; 398: 423-430.
8. Vassileva G, Hu W, Hoos L etal. Gender-dependent effect of Gpbar 1 genetic deletion on the metabolic profiles of diet-induced obese mice. J Endocrinol 2010; 205: 225-232.
9. Sato H, Genet C, Strehle A etal. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaia. Biochem Biophys Res Commun 2007; 48: 1792-1801.
10. Gioiello A, Rosatelli E, Nuti R, Macchiarulo A, Pellicciari R. Patented TGR5 modulators: a review (2006-present). Expert Opin Ther Pat 2012; 22: 1399-1414.
11. Duan H, Ning M, Chen X etal. Design, synthesis, and antidiabetic activity of 4-phenoxynicotinamide and 4-phoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists. J Med Chem 2012; 55: 10475-10489.
12. Eggink HM, Soeters MR, Pols TWH. TGR5 ligands as potential therapeutics in inflammatory diseases. Int J Interf Cyto Med Res 2014; 6: 27-38.
13. Casaburi I, Avena P, Lanzino M etal. Chenodoxycholic acid through a TGR5-dependent CREB signaling activation enhances cyclin D1 expression and promotes human endometrial cancer cell proliferation. Cell Cycle 2012; 11: 2699-2710.
14. Thomas C, Gioiello A, Noriega L etal. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 167-177.
15. 2S. Front Physiol 2014; 5: 420.
16. Li T, Holmstrom SR, Kir S etal. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 2011; 25: 1066-1071.
17. Poole DP, Godfrey C, Cattaruzza F etal. Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil 2010; 23: 995-999.
18. Keitel V, Gorg B, Bidmon HJ etal. The bile acid receptor TGR-5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia 2010; 58: 1794-1805.
19. Kumar D, Rajagopol S, Mahavadi S etal. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells. Biochem Biophy Res Commun 2012; 427: 600-605.
20. Wiang X, Edelstein MH, Gafter U etal. TGR5 expression is decreased in human kidney disease in obesity and diabetes: TGR5 activation inhibits kidney disease in obese and diabetic mice. Diabetes 2015; 64(Suppl.): A21.
21. Desai MS, Shabier Z, Coss-Bu J etal. Modulation of bile acid receptor TGR5: novel therapy for heart failure. Hepatology 2014; 60(Suppl. 1): 819A.
22. Han LY, Fan YC, Mu NN etal. Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B virus associated hepatocellular carcinoma. Int J Med Sci 2014; 11: 164-171.
23. Pols TWH, Noriega LG, Nomura M, Auwerx J, Schoojans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54: 1263-1272.
24. Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 2010; 28: 220-224.
25. Perides G, Laukkarinen JM, Vassileva G, Steer MI. Biliary acute pancreatitis in mice is mediated by the G-protein-coupled cell surface bile acid receptor Gpbar. Gastroenterology 2010; 138: 715-725.
26. Alemi F, Kwon E, Poole DP etal. The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 2013; 123: 1513-1530.
27. Fryer RM, Ng KJ, Nodop Mazurek SG etal. G protein-coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a K(Ca)1.1 (BK(CA))-dependent mechanism. J Pharmacol Exp Ther 2014; 348: 125-130.
28. Kissner T, Stolte M, Czich A etal. Systemic and low systemic available TGR5 agonists lead to histopathological findings in pancreas, liver, and gallbladder. Diabetes 2015; 64(Suppl. 1): A306.
29. Yasuda H, Hirata S, Inoue K, Maxhima H, Ohnishi H, Yoshiba M. Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophy Res Commun 2007; 354: 154-159.
30. Hong J, Behar J, Wands J etal. Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut 2010; 59: 170-180.
31. Pang C, LaLonde AA, Godfrey TE etal. TGR5, a bile acid receptor, is highly expressed in esophageal adenocarcinoma and precancerous lesions significantly associated with worse overall survival and gender difference. Gastroenterol 2015; 148(Suppl. 1): S-354.
32. Buchwald H, Rudser KD, Williams SE, Michalek VN, Vagasky J, Connett JE. Overall mortality, incremental life expectancy, and cause of death at 25 years in the program on the surgical control of the hyperlipidemias. Ann Surg 2010; 251: 1034-1040.
33. Fu ZD, Csanaky IL, Klaassen CD. Gender-divergent profile of bile acid homeostasis during aging of mice. PLoS One 2012; 7: e32551.
34. Fiamoncini J, Frost G, Scheundel R, Daniel H. Gender differences in bile acid kinetics after dietary challenges. FASEB J 2015; 29: S743.5.
35. Ahmad N, Kaplan LM. Gender-specific effects of obesity on the post-prandial rise in circulating bile acids. Obesity 2011; 19(Suppl. 1): S163.
36. Markle JGM, Frank DN, Mortin-Toth S etal. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 2013; 339: 1084-1088.
37. Hodge RJ, Lin J, Vasist Johnson LS, Gould EP, Bowers GD, Nunez DJ. Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes. Clin Pharm Drug Dev 2013; 2: 213-222.
38. Napolitano A, Miller S, Nicholls AW etal. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One 2014; 9: e100778.
39. Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep 2014; 7: 12-18.
40. Pitcher MCL, Cummings JH. Hydrogen sulphide: a bacterial toxin in ulcerative colitis? Gut 1996; 39: 1-4.
41. Magee EA, Richardson CJ, Hughes R, Cummings JH. Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans. Am J Clin Nutr 2000; 72: 1488-1494.
42. Chimeral C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L Cells. Cell Rep 2014; 9: 1202-1208.
43. Kenakin T. The potential for selective pharmacological therapies through biased receptor signaling. BMC Pharmacol Toxicol 2012; 13: 3; DOI: 10.1186/2050-6511-13-3.