Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists

References

• Wilson JE. Hexokinases. Rev Physiol Biochem Pharmacol 1995;126:65–198.
   PubMed Web of Science ®Google Scholar
• Grossbard L, Schimke RT. Multiple hexokinases of rat tissues: purification and comparison of soluble forms. J Biol Chem 1966;241:3546–60.
   PubMed Web of Science ®Google Scholar
• Sarabu R, Taub R, Grimsby J. Glucokinase activation–a strategy for T2D therapy: recent developments. Drug Discov Today 2007;4:111–5.
   Google Scholar
• Matschinsky FM. Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov 2009;8:399–416.
   PubMed Web of Science ®Google Scholar
• Choi JM, Seo MH, Kyeong HH, et al. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc Natl Acad Sci USA 2013;110:10171–6.
   PubMed Web of Science ®Google Scholar
• Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes 2002;51(Suppl 3):S394–S404.
   PubMedGoogle Scholar
• Osbak KK, Colclough K, Saint-Martin C, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Human Mutation 2009;30:1512–26.
   PubMed Web of Science ®Google Scholar
• Lenzen S. A fresh view of glycolysis and glucokinase regulation: history and current status. J Biol Chem 2014;289:12189–94.
   PubMed Web of Science ®Google Scholar
• Iynedjian PB, Mobius G, Seitz HJ, et al. Tissue-specific expression of glucokinase: identification of the gene product in liver and pancreatic islets. Proc Natl Acad Sci USA 1986;83:1998–2001.
   PubMed Web of Science ®Google Scholar
• Del Guerra S, Lupi R, Marselli L, et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 2005;54:727–35.
   PubMed Web of Science ®Google Scholar
• Brown KS, Kalinowski SS, Megill JR, et al. Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus. Diabetes 1997;46:179–86.
   PubMed Web of Science ®Google Scholar
• de la Iglesia N, Mukhtar M, Seoane J, et al. The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. J Biol Chem 2000;275:10597–603.
   PubMed Web of Science ®Google Scholar
• Kaminski MT, Schultz J, Waterstradt R, et al. Glucose-induced dissociation of glucokinase from its regulatory protein in the nucleus of hepatocytes prior to nuclear export. Biochim Biophys Acta 2014;1843:554–64.
   PubMed Web of Science ®Google Scholar
• Pautsch A, Stadler N, Lohle A, et al. Crystal structure of glucokinase regulatory protein. Biochemistry 2013;52:3523–31.
   PubMed Web of Science ®Google Scholar
• Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J 2008;414:1–18.
   PubMed Web of Science ®Google Scholar
• Lloyd DJ, St Jean DJ, Jr., ; Kurzeja RJ, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature 2013;504:437–40.
   PubMed Web of Science ®Google Scholar
• Salgado M, Tarifeno-Saldivia E, Ordenes P, et al. Dynamic localization of glucokinase and its regulatory protein in hypothalamic tanycytes. PLOS One 2014;9:e94035.
   PubMed Web of Science ®Google Scholar
• Elizondo-Vega R, Cortes-Campos C, Barahona MJ, et al. The role of tanycytes in hypothalamic glucosensing. J Cell Mol Med 2015;19:1471–82.
   PubMed Web of Science ®Google Scholar
• Magnuson MA. Tissue-specific regulation of glucokinase gene expression. J Cell Biochem 1992;48:115–21.
   PubMed Web of Science ®Google Scholar
• Moates JM, Nanda S, Cissell MA, et al. BETA2 activates transcription from the upstream glucokinase gene promoter in islet beta-cells and gut endocrine cells. Diabetes 2003;52:403–8.
   PubMed Web of Science ®Google Scholar
• Speck M, Cho YM, Asadi A, et al. Duodenal-jejunal bypass protects GK rats from {beta}-cell loss and aggravation of hyperglycemia and increases enteroendocrine cells coexpressing GIP and GLP-1. Am J Physiol Endocrinol Metab 2011;300:E923–E932.
   PubMed Web of Science ®Google Scholar
• Terauchi Y, Sakura H, Yasuda K, et al. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose(∗). J Biol Chem 1995;270:30253–6.
   PubMed Web of Science ®Google Scholar
• Ferre T, Riu E, Bosch F, Valera A. Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver. Faseb J 1996;10:1213–8.
   PubMed Web of Science ®Google Scholar
• Shiota M, Postic C, Fujimoto Y, et al. Glucokinase gene locus transgenic mice are resistant to the development of obesity-induced type 2 diabetes. Diabetes 2001;50:622–9.
   PubMed Web of Science ®Google Scholar
• Postic C, Shiota M, Niswender KD, et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999;274:305–15.
   PubMed Web of Science ®Google Scholar
• Kamata K, Mitsuya M, Nishimura T, et al. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 2004;12:429–38.
   PubMed Web of Science ®Google Scholar
• Dunten P, Swain A, Kammlott U, et al. Crystal structure of human liver glucokinase bound to a small molecule allosteric activator. Front Diabet 2004;16:145–54.
   Google Scholar
• Spasov AA, Lobasenko VS, Kosolapov VA, et al. Synthesis and pharmacological activity of 3-phenoxybenzoic acid derivatives. Pharma Chem J 2020;54:229–35.
   Web of Science ®Google Scholar
• Meininger GE, Scott R, Alba M, et al. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care 2011;34:2560–6.
   PubMed Web of Science ®Google Scholar
• Ericsson H, Sjöberg F, Heijer M, et al. The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food. Diabet Res Clin Pract 2012;98:436–44.
   PubMed Web of Science ®Google Scholar
• Ramanathan V, Vachharajani N, Patel R, Barbhaiya R. GKM-001, a liver-directed/pancreas-sparing glucokinase modulator (GKM), lowers fasting and post-prandial glucose without hypoglycemia in type 2 diabetic (T2D) patients. Diabetes 2012;61:A76.
   Google Scholar
• Bunkholt Elstrand M, Dong HP, Ødegaard E, et al. Mammalian target of rapamycin is a biomarker of poor survival in metastatic serous ovarian carcinoma. Human Pathol 2010;41:794–804.
   PubMed Web of Science ®Google Scholar
• Bertelsen BI, Steine SJ, Sandvei R, et al. Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer 2006;118:1877–83.
   PubMed Web of Science ®Google Scholar
• Itamochi H, Kigawa J. Clinical trials and future potential of targeted therapy for ovarian cancer. Int J Clin Oncol 2012;17:430–40.
   PubMed Web of Science ®Google Scholar
• Tirmenstein M, Horvath J, Graziano M, et al. Utilization of the Zucker diabetic fatty (ZDF) rat model for investigating hypoglycemia-related toxicities. Toxicol Pathol 2015;43:825–37.
   PubMed Web of Science ®Google Scholar
• Amin NB, Aggarwal N, Pall D, et al. Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes Metab 2015;17:751–9.
   PubMed Web of Science ®Google Scholar
• Denney WS, Denham DS, Riggs MR, Amin NB. Glycemic effect and safety of a systemic, partial glucokinase activator, PF-04937319, in patients with type 2 diabetes mellitus inadequately controlled on metformin-a randomized, crossover, active-controlled study. Clin Pharmacol Drug Dev 2016;5:517–27.
   PubMed Web of Science ®Google Scholar
• Kamimura H, Ito S, Chijiwa H, et al. Simulation of human plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling. Xenobiotica 2017;47:382–93.
   PubMed Web of Science ®Google Scholar
• Hale C, Lloyd DJ, Pellacani A, Véniant MM. Molecular targeting of the GK-GKRP pathway in diabetes. Expert Opin Ther Targets 2015;19:129–39.
   PubMed Web of Science ®Google Scholar
• Kiyosue A, Hayashi N, Komori H, et al. Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:923–30.
   PubMed Web of Science ®Google Scholar
• Grimsby J, Sarabu R, Corbett WL, et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 2003;301:370–3.
   PubMed Web of Science ®Google Scholar
• Georgy A, Zhai S, Liang Z, et al. Lack of potential pharmacokinetic and pharmacodynamic interactions between piragliatin, a glucokinase activator, and simvastatin in patients with type 2 diabetes mellitus. J Clin Pharmacol 2016;56:675–82.
   PubMed Web of Science ®Google Scholar
• Bonadonna RC, Heise T, Arbet-Engels C, et al. Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J Clin Endocrinol Metab 2010;95:5028–36.
   PubMed Web of Science ®Google Scholar
• Sarabu R, Bizzarro FT, Corbett WL, et al. Discovery of piragliatin-first glucokinase activator studied in type 2 diabetic patients. J Med Chem 2012;55:7021–36.
   PubMed Web of Science ®Google Scholar
• Zhi J, Zhai S. Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus. J Clin Pharmacol 2016;56:231–8.
   PubMed Web of Science ®Google Scholar
• Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol 2015;26:88–95.
   PubMed Web of Science ®Google Scholar
• Egan A, Vella A. TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes. Drug Eval. 2019;28:741–7.
   PubMed Web of Science ®Google Scholar
• Vella A, Freeman JLR, Dunn I, et al. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med 2019;11(475).
   Web of Science ®Google Scholar
• Buse JB, Valcarce C, Freeman JL, et al. Simplici-T1—first clinical trial to test activation of glucokinase as an adjunctive treatment for type 1 diabetes. Am Diabetes Assoc 2018;67:126-LB.
   Web of Science ®Google Scholar
• Zhu XX, Zhu DL, Li XY, et al. Dorzagliatin (HMS5552), a novel dual‐acting glucokinase activator, improves glycaemic control and pancreatic β‐cell function in patients with type 2 diabetes: a 28‐day treatment study using biomarker‐guided patient selection. Diabetes Obes Metab 2018;20:2113–20.
   PubMed Web of Science ®Google Scholar
• Zhu D, Gan S, Liu Y, et al. Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Diabetes Endocrinol 2018;6:627–36.
   PubMed Web of Science ®Google Scholar
• Xu H, Sheng L, Chen W, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: results from a first-in-human single ascending dose study. Drug Design Develop Ther 2016;10:1619.
   PubMed Web of Science ®Google Scholar
• Wang P, Liu H, Chen L, et al. Effects of a novel glucokinase activator, HMS5552, on glucose metabolism in a rat model of type 2 diabetes mellitus. J Diabetes Res 2017;2017:1–9.
   Web of Science ®Google Scholar
• Zhu D, Zhang Y, Chen L. 182-OR: a novel dual-acting glucokinase activator (GKA) dorzagliatin (HMS5552) achieved primary efficacy endpoint with good safety profiles in T2DM patients after 24 weeks of treatment in a phase III monotherapy trial. Am Diabetes Assoc 2020;69:182-OR.
   Web of Science ®Google Scholar
• Zhu D, Zhao Y, TANG C, HMM0201 STUDY GROUP, et al. Pharmacodynamics post-hoc analysis of glucose kinase activator dorzagliatin (HMS5552)—twelve weeks treatment in T2D patients in China. Am Diabetes Assoc 2018;67(Supplement_1):1201-P.
   Web of Science ®Google Scholar
• Katz L, Manamley N, Snyder W, et al. AMG 151 (ARRY‐403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. Diabetes Obes Metab 2016;18:191–5.
   PubMed Web of Science ®Google Scholar
• Katz L, Manamley N, Snyder WJ, et al. AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. Diabetes Obes Metab 2016;18:191–5.
   PubMed Web of Science ®Google Scholar
• McVean M, Aicher TD, Boyd SA, et al. In combination therapy of ARRY-403 with metformin, sitagliptin or pioglitazone results in additive glucose lowering in female ZDF rats. Keystone Symposium: Type 2 Diabetes and Insulin Resistance. Banff, AB, Canada, 20–25 January; 2009.
   Google Scholar
• Chung J, Alvarez-Nunez F, Chow V, et al. Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility. J Pharm Sci 2015;104:1522–32.
   PubMed Web of Science ®Google Scholar
• Aicher TD, Anderson D, Boyd SA, et al. ARRY-403, a novel glucokinase activator with potent glucose-dependent anti-hyperglycemic activity in animal models of type 2 diabetes mellitus. Keystone Symposium: Type.
   Google Scholar
• Tsumura Y, Tsushima Y, Tamura A, et al. TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models. PLOS One 2017;12:e0172252.
   PubMed Web of Science ®Google Scholar