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Nov 21, 2013
 |  BC Innovations  |  Cover Story

Glucokinase alternative

Over the last decade, numerous compounds that activate glucokinase have advanced into the clinic to treat diabetes, but the approach has faced safety challenges because of, amongst other issues, high rates of adverse hypoglycemic events. Now, researchers from Amgen Inc. have identified compounds that instead target glucokinase regulator, opening the door to a potentially safer strategy for modulating hepatic glucokinase activity.1

Glucokinase (GCK; GK) catalyzes the conversion of glucose into glucose-6-phosphate, the first step of glycolysis, and is a key regulatory component for maintaining homeostatic levels of glucose in humans. Most of the enzyme is concentrated in the liver, but it also plays a key role in glucose sensing in the pancreas.

Since Roche scientists described the first allosteric GK activator a decade ago,2 diverse classes of compounds have been synthesized and advanced into the clinic as therapies to reduce blood glucose levels in diabetes.3

Although activating GK has been clearly shown to reduce blood glucose levels in patients with diabetes, controlling the effect so as not to tip the balance and cause adverse hypoglycemic events has turned out to be a tall order.4

To address this, companies have designed compounds that only partially agonize GK or have increased selectivity for the liver. A liver-selective GK activator was shown to reduce the occurrence of hypoglycemia in animal models.5 At least eight GK activators remain in the clinic (see "Glucokinase activators in clinical development").

Now, Amgen has taken a different tack to address the problem by targeting not GK but glucokinase regulator (GCKR; GKRP), a GK regulatory subunit present in the liver.

GKRP inhibits GK in...

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