BMS-820132 (Bristol Myers Squibb) is an oral glucokinase (GK) partial activator intended for diabetes. GK activators for diabetes were hotly pursued in the late 2000s, with well over 100 industry patents on GK activators by 2009. The pursuit was triggered by the discovery of the first allosteric activators of glucokinase from an enzymatic screen of 120k compounds at Roche in 2003, leading to the first GK activator studied in diabetes patients. Initial clinical glucokinase full activators [...]

 

Unlike protein kinases, glucokinase (GK, hexokinase IV) phosphorylates glucose to glucose-6-phosphate. GK is not saturated at physiological glucose levels (~5 mM, enzyme Km ~8 mM) allowing it to have a role in “sensing” glucose levels. GK’s role in glucose control and relevance to diabetes is validated by human genetics: loss of function results in a form of diabetes called MODY-2, and gain of function results in persistent hypoglycemia. GK activation reduces blood sugar levels, but too much GK activation can lead to hypoglycemia (low blood sugar).

 

To mitigate the risk of hypoglycemia, the BMS team, like some others, sought “partial” GK activators, rather than “full” activators. A partial GK activator would avoid lowering GK’s glucose Km too much, making GK activity still dependent on physiological glucose concentrations.