Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors

Two small-molecule disruptors of the glucokinase–glucokinase-regulatory-protein complex, AMG-1694 and AMG-3969, are identified that decrease blood glucose levels in various models of hyperglycaemic rodents. Novel glucose-lowering agents 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 increased risk for hypoglycaemia in the clinic. This paper presents an alternative therapeutic point of intervention, focused on the liver-specific GK regulatory protein (GKRP) that binds and inhibits GK in the nucleus. David Lloyd et al . report on a small molecule, AMG-1694, that specifically disrupts the GK–GKRP complex and reduces blood glucose in hyperglycaemic rodent models. Importantly AMG-1694 has no effect in normoglycaemic animals. Disruption of the GK–GKRP complex offers a liver-specific approach of upregulating GK activity in type II diabetes while reducing the risk of hypoglycaemia. Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus 1 . Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate 2 , 3 in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes 4 . In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production 3 , 5 , and is subject to the endogenous inhibitor GK regulatory protein (GKRP) 6 , 7 , 8 . During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus 1 , 9 , 10 . However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators 11 . To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK–GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A