Glucokinase (GK) is an enzyme that converts glucose to glucose-6-phosphate (G6P) and is predominately expressed in pancreatic �-cells and liver hepatocytes. It's endogenous inhibitor, glucokinase regulatory protein (GKRP), binds to and sequesters GK in the nucleus, preventing glucose phosphorylation at fasting. Thus the GK?GK-GKRP equilibrium plays an important role in regulating glucose uptake and glycogen synthesis.  As a result, modulating blood glucose via the GK pathway presents a promising treatment of type II diabetes mellitus (T2DM).  The prevailing approach has focused on compounds that directly hyperactivate GK via allosteric binding (GK activators � GKAs).  One potential liability associated with this class of compounds is the development of hypoglycemia upon alteration of the intrinsic enzyme kinetics of GK.   To mitigate this risk, we explored an alternative mechanism that increases GK-mediated glucose phosphorylation by disrupting the binding of GKRP to GK.  In this presentation, we will describe the identification of a screening hit that led to the discovery of the initial tool compound (AMG-1694) with a suboptimal PK profile. Subsequent metabolic profiling along with structural-based optimization resulted in the discovery of a novel and stable small-molecule GK-GKRP disruptor (AMG-3969).  This compound potently induced the dissociation of the GK-GKRP complex as well as promoted GK translocation in both in vitro and in vivo assays.  Furthermore, AMG-3969 reduced blood glucose levels in rodent models of diabetes while showing no effect in euglycemic animals.  These results represent the first successful discovery of a small molecule that targets the GK-GKRP complex as a novel pathway for managing blood glucose levels with reduced hypoglycemic risk.

Small molecule disruptors of the GK-GKRP interaction as potential antidiabetics

247th National Meeting (2014)

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