Jan 16, 2019 although glucokinase is a known therapeutic target in type 2 diabetes, previous attempts to activate it have not been clinically successful because of side effects and limited efficacy. Glucokinase gk activation as a potential strategy to treat type 2 diabetes t2d is well recognized. Gk is a monomeric enzyme that catalyzes the atpdependent phosphorylation of dglucose to dglucose6phosphate, which is the initial, as well as ratelimiting step, in cellular glucose uptake and metabolism. Present status of clinical deployment of glucokinase. We identified a small molecule gk activator, compound a, that increased the glucose affinity and maximal velocity v max of gk. Other glucokinase activators have produced conflicting results as to whether activation of glucokinase can produce efficacious glucose control without impacting hepatic lipid burden. Glucokinase activators for diabetes therapy diabetes care. The glycolytic pathway is characterized in some cell types 8 10, in pancreatic beta cells 4, 11 and alpha cells, hepatocytes 15 19, certain specific pituitary cells, and brain neurons by a specific feature.
Glucokinase activators offer a potentially promising. Hepatocytes were incubated further for 3 h at 37c, then washed three times in icecold pbs, and. Azd1656 glucokinase activator hexokinase 4 metabolism. Apr 17, 2009 the dosedependent effect of glucokinase activators gkas of high, medium and low potency on glucokinase activity and glucose homeostasis are illustrated by a modelling experiment using.
Arry403, a glucokinase activator with potent glucosedependent antihyperglycemic activity in animal models of type 2 diabetes mellitus. Tmg123, a novel glucokinase activator, exerts durable. Protective effects of glucokinase activator on the onset. Nov 10, 2014 importance of glucokinase in regulating the blood glucose. Lead optimization of an acetylenyl benzamide series led to the discovery of several active compounds via in vitro enzyme assays ec50 glucokinase activators for the potential treatment of type 2 diabetes volume. Glucokinase gk plays a key role in the control of blood glucose homeostasis. Activation of gk was exquisitely sensitive to the chirality of the molecule. Gk glucokinase is an enzyme central to glucose metabolism that displays positive cooperativity to substrate glucose.
Glucokinase gk plays a critical role for maintaining glucose homeostasis. Discovery of piragliatinfirst glucokinase activator studied. Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Thermal stability of glucokinase gk as influenced by the substrate glucose, an allosteric glucokinase activator drug gka and the osmolytes glycerol and urea. Glucokinase gk is a hexokinase isozyme, related homologously to at least three other hexokinases. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy. Although glucokinase is a known therapeutic target in type 2 diabetes, previous attempts to activate it have not been clinically successful because of side effects and limited efficacy. Compound a augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. Assessing the potential of glucokinase activators in. Glucokinase gk, also called hexokinase iv, plays an essential role in blood glucose homeostasis, catalyzing glucose phos phorylation that is the ratelimiting reaction for glycolysis. The network of glucokinaseexpressing cells in glucose. Gk acts as a glucose sensor and elicits glucose specific responses from the respective cell types, e. Identification of mangiferin as a potential glucokinase. The network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy.
Glucokinase activators gkas promise a new pharmacotherapy for diabetics franz m matschinsky1 and daniel porte jr2,3 addresses. Glucokinase activators for diabetes therapy scienceopen. Glucokinase gka activators activatorsinducers, agonists. Jan 10, 2008 glucokinase activators have also demonstrated antidiabetic efficacy in chronic animal models of type ii diabetes. Glucokinase, on the other hand, is primarily a liver enzyme, but is also found on the inner plasma membrane of pancreatic.
Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. We determined the crystal structure of xenopus gk and gkrp. Body weight gain, serum cholesterol levels, serum triglyceride levels and serum free fatty acid levels showed no. Despite the critical roles of gk and gkrp, the molecular basis for the allosteric regulation mechanism of gk by gkrp remains unclear. Due to a recent breakthrough leading to the identification of a novel class of small molecules termed glucokinase activators, the old enzyme became a new target in diabetes therapy. Diabetes copyright 2019 targeting hepatic glucokinase to. Atherogenic, fibrotic and glucose utilising actions of. Regulatory t cell migration is dependent on glucokinase. Glucokinase gk catalyses the formation of glucose 6phosphate from glucose and atp. Ttp355 a glucokinase activator glucokinase gk is an enzyme glucokinase gk is an enzyme localized primarily in pancreatic.
Pdf on may 1, 2011, franz m matschinsky and others published. Mk0941 free base exhibits strong glucoselowering activity and is a potential therapeutic agent for treatment of type 2 diabetes. Targeting hepatic glucokinase to treat diabetes with. Gujral punjab technical university, jalandhar kapurthala highway, kapurthala, punjab, grimt, raduar, yamuna nagar, haryana. Glucokinase activator lowers blood glucose concentrations by enhancing glucose uptake in the liver and increasing insulin production by the pancreatic. Stimulation of hepatocyte glucose metabolism by novel. Glucokinase activators for the potential treatment of type 2. Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators katy j. Stimulation of hepatocyte glucose metabolism by novel small. Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of type 2 diabetes mellitus volume. Assessing the potential of glucokinase activators in diabetes.
The role of glucokinase as a glucose sensor is due for the development of novel glucokinase activators as its allosteric properties. Effect of exogenously administered glucagon versus spontaneous endogenous counterregulation on glycaemic recovery from insulininduced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, azd1656, and metformin. New phase ii data bolster vtv therapeutics glucokinase activator aspirations scrip. The future for glucokinase activation is looking brighter after fresh data on vtvs oral adjunct to insulin therapy in type 1 diabetes. Gk is an emerging target for the therapeutic management of t2d patients as it plays a key function in the regulation of carbohydrate breakdown. Gk activators are the new class of drug candidates which design, synthesis and antidiabetic activity of novel sulfamoyl benzamide derivatives as glucokinase activators.
Pfizers pf 04937319 glucokinase activators for the. Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of type 2 diabetes mellitus authors. Smallmolecule glucokinase activators have been identified that bind to an allosteric site of the enzyme and increase its catalytic activity, thus offering a novel approach to the treatment of type 2 diabetes. All of the hexokinases can mediate phosphorylation of glucose to glucose6phosphate g6p, which is the first step of both glycogen synthesis and glycolysis. Pdf design, synthesis and antidiabetic activity of novel.
Ttp399, a liver selective glucokinase activator gka that. For instance, in a 9day study in obob mice, a glucokinase activator improved the overall glucose profile while showing comparable antihyperglycemic effects in oral glucose tolerance tests at the beginning and end of the study. Us 2041711 a1 urea glucokinase activators the lens. Research paper predictive blood glucose lowering efficacy by glucokinase activators in high fat fed female zucker rats gj coope1, am atkinson1, c allott1, d mckerrecher1, c johnstone1, kg pike1, pc holme2, h vertigan1, d gill1, mp coghlan1 and b leighton1 1cardiovascular and gastrointestinal department, astrazeneca, macclesfield, cheshire, uk and 2syngenta central toxicology. Apr 20, 2017 hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. Efficacy and safety of glucokinase activators for type 2 diabetes mellitus. A fresh view of glycolysis and glucokinase regulation. To improve the effectiveness of the treatment while minimizing adverse reactions such as hypoglycemia, vella et al. Novel acetylenylcontaining benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mm glucose concentration and glucose uptake in rat hepatocytes.
Results this article discusses an overview of t2dm, biology of gk, role of gk in t2dm. Buse3, carmen valcarce2 the therapeutic success of interventions targeting glucokinase gk activation for the treatment of type 2. Coghlan, and loranne agius2 glucokinase gk has a major role in the control of. This enzyme which convert glucose to glucose 6 phosphate exists in two isomer forms. The hepatoselective glucokinase activator pf04991532. Crystal structure determination of human glucokinase in complex with 16a. Novel, highly potent systemic glucokinase activators for the. Unlike hexokinase, glucokinase is not inhibited by its product, glc6p, yet its activity is stimulated by insulin and inhibited by diabetogenic hormones e.
Ro281675 also reversed the inhibitory action of the human glucokinase regulatory protein gkrp 14 fig. Pdf glucokinase is a member of the hexokinase family of enzymes that are. This is the expression of a fourth hexokinase isoenzyme. After 10 days acclimation, diabetic mice were randomly divided into there. Predictive blood glucose lowering efficacy by glucokinase. Apr 22, 2011 the network of glucokinaseexpressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Glucokinase inhibitors agonists modulators antagonists. An allosteric activator of glucokinase impairs the. Jun 18, 20 glucokinase gk is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. Its expression is limited to the major organs such as the pancreas, liver, brain and the gastrointestinal tract that are thought. Us 20090054444 a1 substituted phenylacetamides and their. Antidiabetic agents, type 2 diabetes, allosteric activator, glucokinase activators abstract. Identification of mangiferin as a potential glucokinase activator by. Ampk activators 14 autophagy inducers 3 cell stimulation cocktails 2 channel openers 2 dreadd agonists 2 ferroptosis activators glucokinase gka activators 1 guanylyl cyclase activators 8 hat activators 1 hedgehog signaling pathway agonists 6 integrin agonists 1 nlrp3 inflammasome activators 4 oct34 inducers 1 p53.
Vanderkooi, phd 1 ali naji, phd, md 3 ramakanth sarabu, phd 4 joseph grimsby, phd 4 t ype 2 diabetes is characterized by elevated blood glucose levels resulting from a. Human gk isoform 3 cocrystals that belonged to the p6522 space group were generated with numerous gk activators in the presence of glucose in hanging drop trays in 100mm hepes ph 7. Recent updates on glucokinase activators for the treatment of type 2 diabetes mellitus. Since pf04991532 is a selective liver activator, we were able to evaluate the effect of exclusively hepatic glucokinase activation. Type 2 diabetes is characterized by elevated blood glucose levels resulting from a pancreatic. Smallmolecule gkas gk activators modulate gk catalytic activity and glucose affinity and are currently being pursued as a treatment for type 2 diabetes. The medium was renewed and 74 kbqml1 du14c glucose plus vehicle or compound 0. Glucokinase gk, hexokinase iv plays a unique role in glucose homeostasis. Overall, the available data suggests that potent glucokinase activators with the desired effects on the kinetic properties of the enzyme can be designed to achieve strong and persistent antidiabetic effects. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Glucokinase is ex pressed in a variety of tissues including liver hepatocytes and pancreatic. 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. New phase ii data bolster vtv therapeutics glucokinase. Glucokinase activators gkas are novel agents for diabetes which act by enhancing the formation of glucose6phosphate leading to increased insulin.
Pdf recent advances in glucokinase activators for the treatment of. Glucokinase is very important in the regulation of insulin secretion and has been known as the pancreatic betacell sensor. Pdf recent advances in glucokinase activators for the. Histological analysis showed that genetic activation of glucokinase in the. If untreated, diabetic complications develop that cause loss of vision, peripheral neuropathy, impaired kidney function, heart disease, and stroke. A novel glucokinase activator ro4389620 improved fasting and postprandial plasma glucose in type 2 diabetic. Glucokinase is one of four members of the hexokinase family of enzymes. Mice had free access to water and food throughout the study period.
Several glucokinase activators gkas are presently at various stages of clinical development. Pdf glucokinase activators for diabetes therapy researchgate. Both of these enzymes are iso enzymes, which means that both of them have the same chemical natures and have same action but have different physical properties and site of action etc. Guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in.
Targeting hepatic glucokinase to treat diabetes with ttp399, a hepatoselective glucokinase activator adrian vella1, jennifer l. Discovery of piragliatinfirst glucokinase activator. Design and synthesis of acetylenyl benzamide derivatives. Thus, small molecule glucokinase activators have been demonstrated to be effective glucoselowering agents in animal models of type 2 diabetes and have advanced. Glucokinase in beta cells serves as a glucose sensor, amplifying insulin secretion as blood glucose rises. The renantiomer was a potent activator with an ec 50 of 0. The lens serves almost all the patents and scholarly work in the world as a free, open and secure digital public good, with user privacy a paramount focus. Modulation of glucokinase by glucose, smallmolecule. Glucokinase activators for diabetes therapy may 2010 status report franz m.
Glucokinase have a single allosteric site where the glucoseregulating protein gkrp binds in the nucleus of the cell in its inactive form when there is a low concentration of glucose present in the cell. The glucosephosphorylating enzyme glucokinase has structural, kinetic, and molecular genetic features that are ideal for its primary role as glucose sensor in a network of neuroendocrine sentinel cells that maintain glucose homeostasis in many vertebrates including humans. Present status of clinical deployment of glucokinase activators. Role of glucokinase in regulation of physiological insulin secretion from pancreatic beta cells. Gk progress curves monitoring product formation are linear up to 1 mm glucose, but biphasic at 5 mm, with the transition. Kishore and colleagues demonstrate that treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a treg cellselective pi3kmtorc2 pathway. Glucokinase activators for diabetes therapy europe pmc. Glucokinase activators gkas promise a new pharmacotherapy for diabetics. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis. Vanderkooi, phd 1 ali naji, phd, md 3 ramakanth sarabu, phd 4 joseph grimsby, phd 4 t ype 2 diabetes is characterized by elevated blood glucose levels result. Recent updates on glucokinase activators and glucokinase.
New hope for glucokinase activators in type 2 diabetes. Hexokinase or glucokinase is an enzyme that convert glucose to glucose 6 phosphate. We hypothesized that the hepatic lipidosis was due to the structurebased toxicity and later established that it was due to the formation of. A specific feature of gk amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns gk into a unique key sensor of glucose metabolism, notably in the pancreas. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the. Regulatory t cell localization to inflammatory sites is key to their homeostatic function. What is the difference between hexokinase and glucokinase. 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. Allosteric activation of human glucokinase diginole. Present status of clinical deployment of glucokinase activators ncbi. Compound 1, a glucokinase activator gka lead that we have previously disclosed, caused reversible hepatic lipidosis in repeatdose toxicology studies. Targeting hepatic glucokinase to treat diabetes with ttp399. Metabolic and vascular department, roche, nutley, nj 07110, usa. We report here the mechanism of action of two novel and potent direct activators of gk.
Due to this, glucokinase and glucokinase activators are the focus of treatment for those with type 2 diabetes mellitus. The r enantiomer, ro281675, was a potent gka, whereas the s enantiomer, ro281674, was inactive fig. 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. Gk activators thus represent a promising new treatment for type 2 diabetes. The most recent study of a glucokinase activator is that of dorzagliatin, administered in increasing doses to 258 people with t2d over a 12. Aug 14, 2012 several glucokinase activators gkas are presently at various stages of clinical development. 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. One atp molecule is cleaved to adp and the phosphate released is added to glucose. Glucokinase and the potential of glucokinase activation in. Gujral punjab technical university, jalandhar kapurthala highway, kapurthala, punjab, india manish kaushik. In humans, the glucokinase gene gck is located on chromosome 7p15. Ttp355 a glucokinase activator american diabetes association.
Mk0941 free base is an orally active glucokinase activator, with ec 50 s of 240 and 65 nm for recombinant human glucokinase in the presence of 2. This application relates to novel urea glucokinase activators and use of the compounds of the invention for preparation of a medicament for the treatment of various diseases, e. Mar 20, 2017 the natural product mangiferin compound 7 has been identified as a potential glucokinase activator by structurebased virtual ligand screening. We describe a class of antidiabetic agents that act as nonessential, mixedtype gk activators gkas that increase the glucose affinity and maximum velocity v max of gk. Therefore, very little free glucose is normally absorbed by the ruminant intestinal tract to induce this hepatic enzyme. Gk is regulated by gk regulatory protein gkrp, and indirectly by allosteric effectors of gkrp. Glucokinase gk has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. Effects of a novel glucokinase activator, hms5552, on. The activity of glucokinase ex a new treatment for diabetes. Akita mice were also challenged with diet containing 0. Even if glucokinase activators such as dorzagliatin succeed in being commercialised, their positioning among the armamentarium of medications already available for the treatment of type 2 diabetes will depend on comparative efficacy and safety profiles, ease of use especially with twice daily administration, and cost. Molecular basis for the role of glucokinase regulatory.
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