Inhibition of the Enzyme PEPCK as Therapeutic Approach to Treating Diabetes

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PEPCK is an enzyme critical in the process of gluconeogenesis whose inhibition could be used to treat hyperglycemia and diabetes.


PEPCK catalyzes the first committed step in hepatic gluconeogenesis and is a key regulator of blood glucose homeostatis. Overexpression of this enzyme results in pre-diabetes and diabetes. PEPCK expression is stimulated by glucagon, glucocorticoids, retinoic acid and adenosine 3', 5'-monophosphate (cAMP) and is inhibited predominantly by insulin. Insulin levels of diabetic patients are insufficient to adequately inhibit PEPCK. Inhibition of PEPCK with siRNA led to complete elimination of hyperglycemia in a diabetic mouse model.

Inhibition of Phosphoenolpyruvate caroxykinase (PEPCK) is a promising new therapeutic approach to treating diabetes and preventing diabetic complications such as circulatory problems, heart disease, and blindness. The novel compounds are highly selective for PEPCK and can be used to treat both acute hyperglycemia and secondary long-term complications from hyperglycemia. The invention covers both composition of matter and a scaffold to allow for chemical substitutions that provide functionalities to participate in as many interactions with PEPCK as possible.
Licensing Associate: 
Aswini Betha, PhD · · 913-588-5713
Todd Holyoak
Gerald Carlson
Rose Mary Stiffin
Sarah Sullivan
US 8,673,584