Pdf on may 1, 2011, franz m matschinsky and others published glucokinase activators for diabetes therapy find, read and cite all the research you need on researchgate. They also curbed hepatic glucose production in normal and diabetic rats. Several glucokinase activators gkas are presently at various stages of clinical development. Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10.
Production and purification of gk recombinant proteins has been described previously. Conformational sampling was based on the monte carlo procedure, and. Constraints imposed by comorbidities notably cardiovascular disease and renal impairment and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. Exploring the in vivo mechanisms of action of glucokinase. Forest licenses transtechs glucokinase activators the. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased insulin secretion and liver glycogen synthesis. Where sigma product or stock numbers are specified. As such, attempts to discover glucokinase activators suitable for clinical development have. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased insulin secretion and liver glycogen synthesis and a decrease in liver glucose output. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or. Understanding the conformational changes of gk during the reaction is crucial for designing better glucokinase activators with safer profiles. Pdf glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the. Present status of clinical deployment of glucokinase activators.
Discovery of piragliatinfirst glucokinase activator. Allosteric activation of human glucokinase diginole. Glucokinase activators gkas promise a new pharmacotherapy for diabetics franz m matschinsky1 and daniel porte jr2,3 addresses. Glucokinase gka activators activatorsinducers, agonists. A liverselective gk activator bms922212 has also been developed but not studied in humans to date. Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a sigmoidal saturation curve for its substrate, two properties that are important for its playing the role of a glucose sensor in pancreas and liver. Allosteric glucokinase activators gkas were discovered by highthroughput screening of a large compound library and first reported in 2003. Assessing the potential of glucokinase activators in diabetes therapy. Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. Investigation of functionally liver selective glucokinase. Recent updates on glucokinase activators for the treatment of type.
Glucokinase activators offer a potentially promising. Glucokinase activators gkas in diabetes management. The molecular basis for these two properties is not well understood. Discovery of piragliatinfirst glucokinase activator studied. Glucokinase activators gkas promise a new pharmacotherapy. Several of the reported chemotypes possess structural features that diverge from known leads. Jones, b brendan leighton, a darren mckerrecher, a kurt g. The glucosephosphorylating enzyme glucokinase gk was identified as an outstanding drug target for developing antidiabetic medicines. Glucokinase activation ameliorates er stressinduced. Crystal structure of human glucokinase in complex with a small molecule activator.
Future glucoselowering drugs for type 2 diabetes the. This enzyme which convert glucose to glucose 6 phosphate exists in two isomer forms. Small molecules called glucokinase activators gkas which bind to an. The limited tissue expression and unique kinetic properties of gk allow it to play a critical role in pancreatic. Glucokinase activators pharmaceutical patent analyst. A small molecule glucokinase activator lowers blood glucose in rats desensitized to sulfonylurea agents sulfonylureas sfus are insu sulfonylureas sfus are insulin secretagogues.
Interest in glucokinase activators, a class of diabetes compounds with a rocky past, appears to be reviving. M, respectively, for the recombinant enzymes, which translates into cellular systems ec50s 1. Apr 20, 2017 hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Human glucokinase gk is a principal regulating sensor of plasma glucose levels. Glucokinase gk activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. Gk catalyzes the phosphorylation of glucose to glucose 6phosphate, which triggers glucose utilization and cellular metabolism. At 1 mm glucose, glucagon secretion by islets from 18. Pdf designing glucokinase activators with reduced hypoglycemia. A small molecule glucokinase activator lowers blood glucose. Chronic treatment with sfus leads to a decline in their insulinotropic activity, likely attributed to desensitization of. Gkrp binds and moves glucokinase gk, thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism.
In humans, the glucokinase gene gck is located on chromosome 7p15. In a longterm study with c57bl6j mice, gkas had the remarkable result of preventing the development of dietinduced diabetes with little effect on the weight gain of the animals. Glucokinase is very important in the regulation of insulin secretion and has been known as the pancreatic betacell sensor. One atp molecule is cleaved to adp and the phosphate released is added to glucose. In intact control animals and a wide variety of animal models of type 2 diabetes, gkas lowered blood glucose and stimulated insulin release. Mutations in glucokinase gk gene results in maturity onset diabetes of the young 2 mody2. Nov 10, 2014 importance of glucokinase in regulating the blood glucose. Glucokinase, on the other hand, is primarily a liver enzyme, but is also found on the inner plasma membrane of pancreatic. The disclosure of pharmacological glucokinase activator gka. Glucokinase activation ameliorates er stressinduced apoptosis in pancreatic. Aug 14, 2015 the impairment of glucose homeostasis leads to hyperglycemia and type2 diabetes mellitus. Importance of glucokinase in regulating the blood glucose. Glucokinase and glucokinase regulatory proteins as.
A small molecule glucokinase activator lowers blood. Glucokinase functions only in emergencies, when the concentration of. The renantiomer was a potent activator with an ec 50 of 0. The impairment of glucose homeostasis leads to hyperglycemia and type2 diabetes mellitus. Chronic treatment with sfus leads to a decline in their insulinotropic activity, likely attributed to desensitization of betacells to these drugs. The deal includes the rights to ttp399, which is poised to start phase ii. Atherogenic, fibrotic and glucose utilising actions of. Briefly, the assay was performed in the presence of serial dilutions of test compounds, 5 mmoll glucose and 1 mmoll atp. Antidiabetic effects of glucokinase regulatory protein. It is coded for by a 19 exon gene, gckr, on the short arm. Mutations that inactivate gk are linked to diabetes, and.
In the pancreatic betacell, glucokinase is a key regulator enzyme. Structural basis for allosteric regulation of the monomeric. Glucokinase hexokinase iv continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. We hypothesized that the hepatic lipidosis was due to the structurebased toxicity and later established that it was due to the formation of. Glucokinase activator, type 2 diabetes, ttp399, glucose metabolism. Chronic glucokinase activation reduces glycaemia and. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis.
The present study is aimed to identify the binding mode of pyridone deriva. Glucokinase gk plays a critical role in the control of wholebody glucose homeostasis. Glucokinase activators gkas have been shown to reduce blood glucose levels in. Pdf recent advances in glucokinase activators for the treatment of. Since 2003, many glucokinase activators gkas have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Pfizers pf 04991532 a hepatoselective glucokinase activator. Comparative docking assessment of glucokinase interactions. Compounds were imported into icm and an index file was created. Herein we report the crystal structures of glucokinase in its active and inactive forms, which. The glucosephosphorylating enzyme glucokinase, a promising target for developing new antidiabetic agents, was identified through the combined efforts of basic research and human biochemical genetics.
Pdf present status of clinical deployment of glucokinase. Ttp355 a glucokinase activator american diabetes association. Glucokinase gk is involved in the regulation of glucose homeostasis and is an important target for drug discovery against diabetes, but some current gk activators are associated with an. Recent advances in glucokinase activators for the treatment. Since 2003, various types of gk activators have been discovered, and their efficacy to decrease the blood sugar was reported in various animal models of t2dm 11,434470. Aug 14, 2012 several glucokinase activators gkas are presently at various stages of clinical development. Effects of glucokinase activators gka50 and ly2121260 on. Ttp399 is a hepatoselective, glucokinase activator with potential for treating type. Glucokinase activators with improved physicochemicalproperties and off target effects american chemical society national meeting and exposition kirman lc, schuster hf, grondine ms et al 2010 240th august 22 medi197 investigation of functionally liver selective glucokinase activators american chemical society national meeting and exposition. Molecular docking of pds as gkas nanda kumar et a original. In humans, activating mutations of glucokinase have been described, resulting in hyperinsulinemic hypoglycaemia cuestamunoz et al. Researcharticle effects of a novel glucokinase activator, hms5552, on glucose metabolism in a rat model of type 2 diabetes mellitus pingwang,1 huililiu,2 lichen,3.
Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises. Effects of a novel glucokinase activator, hms5552, on glucose. Finally, a number of in vitro and acute studies have shown that small molecule glucokinase activators. Apr 22, 2011 the network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Antidiabetic effects of glucokinase regulatory protein small. Published in august 2010 by cambridge healthtech institute. Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occuring mutations vladi v. Current chemical genomics and translational medicine discontinued issn. Glucokinase gk plays a critical role for maintaining glucose homeostasis with. In hepatocytes, gk controls the glucose uptake and glycogen synthesis. Brogan, b matthew coghlan, a craig johnstone, a huw b. Designing glucokinase activators with reduced hypoglycemia risk.
In hepatocytes, gk controls the glucose uptake and glycogen. Ttp355 a glucokinase activator glucokinase gk is an enzyme glucokinase gk is an enzyme localized primarily in pancreatic. Male spraguedawley sd rats were divided into four groups. The half effective concentration ec 50 and v max values of the gkas were determined using a pyruvate kinaselactate dehydrogenasecoupled assay. Glucokinase gk activation as a potential strategy to treat type 2 diabetes t2d is well recognized. Abstract human glucokinase gk is a principal regulating sensor of plasma glucose levels. Glucokinase mechanism of action and biological processes. Gkrp binds and moves glucokinase gk, thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism gkrp is a 68 kd protein of 626 amino acids. Bms8202 is considered to be safe and generally welltolerated in patients with t2dm over the dose range studied up to 450 mg with pkpd properties amenable to once or twice daily dosing. Glucokinase, a member of the hexokinase family, is mainly expressed in hepatocytes, pancreatic. Glucokinase activators gkas are novel agents for diabetes which act by enhancing the formation of glucose6phosphate leading to increased insulin. Azd1656 glucokinase activator hexokinase 4 metabolism. The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucoselowering drugs.
Effects of a novel glucokinase activator, hms5552, on. The normal plasma glucose set point of approximately 5 m m is dependent on the activity of glucokinase gk, which senses glucose and controls metabolic flux in certain key cell types 46. Nov, 20 glucokinase gk is involved in the regulation of glucose homeostasis and is an important target for drug discovery against diabetes, but some current gk activators are associated with an. Small molecule activators of the glucokinase enzyme have the potential to deliver a level of glycaemic control that is superior to current oral agents and hence have great promise as new therapies for type 2 diabetes. Glucokinase gk, an enzyme that catalyzes the conversion of glucose to glucose6phosphate in pancreatic. Matrixbased multiparameter optimisation of glucokinase. Tmg123, a novel glucokinase activator, exerts durable. Compound 1, a glucokinase activator gka lead that we have previously disclosed, caused reversible hepatic lipidosis in repeatdose toxicology studies.
The glucokinase regulatory protein gkrp also known as glucokinase hexokinase 4 regulator gckr is a protein produced in hepatocytes liver cells. A gk activator has the promise of potentially affecting both the. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. We investigated the possible effects of a novel glucokinase activator gka, hms5552, to the gk in rats with type 2 diabetes mellitus t2dm. Jul 26, 2012 glucokinase activators as potential antidiabetic agents possessing superior glucoselowering efficacy. Identification of mangiferin as a potential glucokinase activator by. Azd1656 is a potent, selective 100fold versus hexokinase 1 and 2 and a pharmacology screening panel, activator of human and rat glucokinase in vitro. Glucokinase and glucokinase regulatory proteins as molecular. Glucokinase functions only in emergencies, when the concentration of glucose in the blood rises to abnormally high levels. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the.
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