A small molecule glucokinase activator lowers blood glucose in rats desensitized to sulfonylurea agents sulfonylureas sfus are insu sulfonylureas sfus are insulin secretagogues. 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. Molecular docking of pds as gkas nanda kumar et a original. Comparative docking assessment of glucokinase interactions. Apr 22, 2011 the network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Present status of clinical deployment of glucokinase activators. Mutations in glucokinase gk gene results in maturity onset diabetes of the young 2 mody2. We investigated the possible effects of a novel glucokinase activator gka, hms5552, to the gk in rats with type 2 diabetes mellitus t2dm. Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occuring mutations vladi v. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the. Matrixbased multiparameter optimisation of glucokinase.
The limited tissue expression and unique kinetic properties of gk allow it to play a critical role in pancreatic. The half effective concentration ec 50 and v max values of the gkas were determined using a pyruvate kinaselactate dehydrogenasecoupled assay. Glucokinase, a member of the hexokinase family, is mainly expressed in hepatocytes, pancreatic. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis. Recent advances in glucokinase activators for the treatment. Understanding the conformational changes of gk during the reaction is crucial for designing better glucokinase activators with safer profiles. Pfizers pf 04991532 a hepatoselective glucokinase activator. A liverselective gk activator bms922212 has also been developed but not studied in humans to date. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. 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. Abstract human glucokinase gk is a principal regulating sensor of plasma glucose levels.
Glucokinase, on the other hand, is primarily a liver enzyme, but is also found on the inner plasma membrane of pancreatic. In hepatocytes, gk controls the glucose uptake and glycogen synthesis. Glucokinase gk activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. Future glucoselowering drugs for type 2 diabetes the. Allosteric glucokinase activators gkas were discovered by highthroughput screening of a large compound library and first reported in 2003. 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. Present status of clinical deployment of glucokinase activators ncbi. Mutations that inactivate gk are linked to diabetes, and. A gk activator has the promise of potentially affecting both the. 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. A small molecule glucokinase activator lowers blood. 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.
Apr 20, 2017 hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Gk catalyzes the phosphorylation of glucose to glucose 6phosphate, which triggers glucose utilization and cellular metabolism. 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. Jul 26, 2012 glucokinase activators as potential antidiabetic agents possessing superior glucoselowering efficacy. 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.
Pdf recent advances in glucokinase activators for the treatment of. Human glucokinase gk is a principal regulating sensor of plasma glucose levels. Current chemical genomics and translational medicine discontinued issn. Glucokinase activators pharmaceutical patent analyst. Jones, b brendan leighton, a darren mckerrecher, a kurt g. 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.
Recent updates on glucokinase activators for the treatment of type. Discovery of piragliatinfirst glucokinase activator studied. Glucokinase gk, an enzyme that catalyzes the conversion of glucose to glucose6phosphate in pancreatic. Aug 14, 2015 the impairment of glucose homeostasis leads to hyperglycemia and type2 diabetes mellitus. Pdf glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the. We hypothesized that the hepatic lipidosis was due to the structurebased toxicity and later established that it was due to the formation of. Chronic treatment with sfus leads to a decline in their insulinotropic activity, likely attributed to desensitization of. Production and purification of gk recombinant proteins has been described previously. Atherogenic, fibrotic and glucose utilising actions of. The deal includes the rights to ttp399, which is poised to start phase ii. Pdf present status of clinical deployment of glucokinase. Glucokinase gk plays a critical role for maintaining glucose homeostasis with. Glucokinase and glucokinase regulatory proteins as. Glucokinase activators offer a potentially promising.
Antidiabetic effects of glucokinase regulatory protein small. Glucokinase gka activators activatorsinducers, agonists. Ttp399 is a hepatoselective, glucokinase activator with potential for treating type. Interest in glucokinase activators, a class of diabetes compounds with a rocky past, appears to be reviving. Male spraguedawley sd rats were divided into four groups. The impairment of glucose homeostasis leads to hyperglycemia and type2 diabetes mellitus. 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. 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. Effects of glucokinase activators gka50 and ly2121260 on. Chronic glucokinase activation reduces glycaemia and.
One atp molecule is cleaved to adp and the phosphate released is added to glucose. Several of the reported chemotypes possess structural features that diverge from known leads. Several glucokinase activators gkas are presently at various stages of clinical development. 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 occurs in cells in the liver and pancreas of humans and most other vertebrates. Gkrp binds and moves glucokinase gk, thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism.
Glucokinase activator, type 2 diabetes, ttp399, glucose metabolism. Exploring the in vivo mechanisms of action of glucokinase. As such, attempts to discover glucokinase activators suitable for clinical development have. Glucokinase activators gkas promise a new pharmacotherapy. The present study is aimed to identify the binding mode of pyridone deriva. Chronic treatment with sfus leads to a decline in their insulinotropic activity, likely attributed to desensitization of betacells to these drugs. Designing glucokinase activators with reduced hypoglycemia risk. Compound 1, a glucokinase activator gka lead that we have previously disclosed, caused reversible hepatic lipidosis in repeatdose toxicology studies. Glucokinase mechanism of action and biological processes.
In intact control animals and a wide variety of animal models of type 2 diabetes, gkas lowered blood glucose and stimulated insulin release. 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. Assessing the potential of glucokinase activators in diabetes therapy. Compounds were imported into icm and an index file was created. In the pancreatic betacell, glucokinase is a key regulator enzyme. These challenges have prompted the development of new. Crystal structure of human glucokinase in complex with a small molecule activator. Glucokinase activators gkas are novel agents for diabetes which act by enhancing the formation of glucose6phosphate leading to increased insulin. Here we describe the research and development of a process for the practical synthesis of glucokinase activator r1 as a potential drug for treating type2 diabetes. Conformational sampling was based on the monte carlo procedure, and. Structural basis for allosteric regulation of the monomeric. At 1 mm glucose, glucagon secretion by islets from 18. 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.
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. Activators of glucokinase increase the sensitivity of the enzyme to glucose, leading to increased insulin secretion and liver glycogen synthesis. Glucokinase activators gkas promise a new pharmacotherapy for diabetics franz m matschinsky1 and daniel porte jr2,3 addresses. Discovery of piragliatinfirst glucokinase activator. 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. Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. Investigation of functionally liver selective glucokinase. In humans, activating mutations of glucokinase have been described, resulting in hyperinsulinemic hypoglycaemia cuestamunoz et al. Nov 10, 2014 importance of glucokinase in regulating the blood glucose. They also curbed hepatic glucose production in normal and diabetic rats. Ttp355 a glucokinase activator american diabetes association. 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 activation ameliorates er stressinduced. Forest licenses transtechs glucokinase activators the.
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. Identification of mangiferin as a potential glucokinase activator by. Glucokinase gk activation as a potential strategy to treat type 2 diabetes t2d is well recognized. The glucosephosphorylating enzyme glucokinase gk was identified as an outstanding drug target for developing antidiabetic medicines. Glucokinase functions only in emergencies, when the concentration of. Glucokinase activators gkas have been shown to reduce blood glucose levels in. Thus, small molecule glucokinase activators have been demonstrated to be effective glucoselowering agents in animal models of type 2 diabetes and have advanced. Importance of glucokinase in regulating the blood glucose.
The disclosure of pharmacological glucokinase activator gka. Glucokinase activators gkas in diabetes management. Briefly, the assay was performed in the presence of serial dilutions of test compounds, 5 mmoll glucose and 1 mmoll atp. The molecular basis for these two properties is not well understood. In hepatocytes, gk controls the glucose uptake and glycogen. Glucokinase is very important in the regulation of insulin secretion and has been known as the pancreatic betacell sensor. 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. Glucokinase and glucokinase regulatory proteins as molecular. Azd1656 is a potent, selective 100fold versus hexokinase 1 and 2 and a pharmacology screening panel, activator of human and rat glucokinase in vitro. This enzyme which convert glucose to glucose 6 phosphate exists in two isomer forms. Effects of a novel glucokinase activator, hms5552, on glucose. Glucokinase gk plays a critical role in the control of wholebody glucose homeostasis.
Antidiabetic effects of glucokinase regulatory protein. M, respectively, for the recombinant enzymes, which translates into cellular systems ec50s 1. Small molecules called glucokinase activators gkas which bind to an. Pdf designing glucokinase activators with reduced hypoglycemia. Glucokinase functions only in emergencies, when the concentration of glucose in the blood rises to abnormally high levels. A small molecule glucokinase activator lowers blood glucose. It is coded for by a 19 exon gene, gckr, on the short arm. Azd1656 glucokinase activator hexokinase 4 metabolism. Tmg123, a novel glucokinase activator, exerts durable. Published in august 2010 by cambridge healthtech institute. Ttp355 a glucokinase activator glucokinase gk is an enzyme glucokinase gk is an enzyme localized primarily in pancreatic. Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises. Where sigma product or stock numbers are specified. Brogan, b matthew coghlan, a craig johnstone, a huw b.
The renantiomer was a potent activator with an ec 50 of 0. Aug 14, 2012 several glucokinase activators gkas are presently at various stages of clinical development. The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucoselowering drugs. It has been observed that gk activators gkas can activate gk structure and promote glucose phosphorylation and bring blood glucose levels to normal condition. The glucokinase regulatory protein gkrp also known as glucokinase hexokinase 4 regulator gckr is a protein produced in hepatocytes liver cells. Finally, a number of in vitro and acute studies have shown that small molecule glucokinase activators. Glucokinase activation ameliorates er stressinduced apoptosis in pancreatic. Herein we report the crystal structures of glucokinase in its active and inactive forms, which. Hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Present status of clinical deployment of glucokinase. 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. Effects of a novel glucokinase activator, hms5552, on.
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