Therapeutics: Glucokinase (GCK; GK); glucokinase regulator (GCKR; GKRP)

In vitro and rat studies suggest a thiazole sulfone-based disruptor of the GCK-GCKR complex could help treat Type II diabetes. Chemical synthesis and in vitro testing of aryl sulfone analogs identified a lead thiazole sulfone that inhibited GCK-GCKR binding with an IC50 of 6 nM. In a rat hepatocyte-based assay of GCKR-mediated nuclear translocation and inactivation of GCK, the lead compound promoted translocation of GCK to the cytoplasm with an EC50 of 0.10 µM. In rats, oral 100 mg/kg doses of the lead compound induced 100% translocation of GCK to the cytoplasm of liver cells within 6 hours, and the compound had 80% oral bioavailability and an IV half-life of 4.7 hours. Next steps could include testing the lead compound in animal models of diabetes.

Pfizer Inc. has PF-04937319, a partial GCK activator, in Phase II testing to treat Type II diabetes...