Glucokinase (GKA) is an enzyme that facilitates removal of glucose in circulation and functions as a glucose sensor mainly in the liver and pancreas cells. GKAs have been shown as an effective strategy to lower glucose in animal models and patients with T2DM. By selectively activating the enzymatic activity in the liver, a liver-specific GKA can significantly reduce the risk of hypoglycemia that was observed with earlier generation of GKAs. Taking advantage of the HepDirect technology, Ligand has identified a lead compound series that demonstrated potent glucose-lowering activity in animal models without causing hypoglycemia mediated mainly through pancreas activity.