Midway through National Diabetes Month, researchers report the discovery of two small molecules that could lead to new treatments for Type 2 diabetes.
About 25.8 million people in the United States have diabetes, according to the Centers of Disease Control and Prevention. An enzyme called glucokinase plays an important role in holding blood glucose levels steady. It converts glucose to glucose-6-phosphate in various organs, such as the pancreas and the liver.
Glucokinase is a compelling drug target to control blood glucose levels. Efforts have focused on drugs that work as glucokinase activators to keep glucokinase turned on. But, as David Lloyd of Amgen explains, a drawback with these drugs has been severe hypoglycemia (too little glucose in the blood).
Lloyd and colleagues decided to take the opposite approach and target a liver-based glucokinase inhibitor called glucokinase regulatory protein. “GKRP inhibitory control over glucokinase via its direct interaction has been well documented. Recent genomewide association studies have uncovered GKRP’s association with common Type 2 diabetes,” explains Lloyd. “The main hurdle we faced was that no small molecule has ever been identified that directly targeted glucokinase regulatory protein.”
As they describe in their Nature paper, the investigators screened for compounds that targeted the interactions between glucokinase and GKRP. They found two molecules, AMG-1694 and AMG-3969, that disrupted the interaction between glucokinase and GKRP. The disruption kept glucokinase active in only the liver. “The liver-specific mechanism may spare the pancreas from increased insulin secretion associated with current glucokinase activators in clinical trials,” says Lloyd.
The work is significant because GKRP “had previously been considered intractable,” says Lloyd. “We determine that GKRP now is a bona fide target for the potential treatment for Type 2 diabetes.”
He says an important step was that he and his colleagues solved the structure of GKRP bound to AMG-1694 and AMG-3969 and identified “a pocket occupied by our molecules.” Lloyd adds that the identification of the pocket allowed the investigators to tweak their compounds for a better fit to the pocket and make the compounds more potent.
But Lloyd cautions the compounds still need to be tested in humans. “In general, a rodent model is a crude representation of the human disease,” he says. “We tested our molecules in several distinct rodent models of diabetes to get a general picture of their effects” under different in genetic and nutritional conditions.
Lloyd adds by testing the molecules in several models allowed “us to gain confidence in the efficacy of the molecules. However, we still cannot make conclusions on their translation to the human disease.”
