Targeting the glucokinase (GK) pathway for the treatment of diabetes is an attractive approach, particularly as small molecule activators of GK have shown robust efficacy in the clinic. However, over-activation can lead to excessive glucose turnover, and hypoglycemia is an acknowledged on-target liability.  An alternate strategy to target the endogenous inhibitor of GK, namely glucokinase regulatory protein (GKRP), could avoid this undesired side-effect as inherent enzyme kinetics would remain unaltered.  Toward this end, we identified compounds that disrupted the GK-GKRP interaction, and will discuss a structure-based design approach to optimizing these initial leads.  Subsequent in vivo studies demonstrated that selectively targeting GK-GKR disruption produced an on-target pharmacodynamic effect associated with a reduction in glucose and no observable hypoglycemia in normal and diabetic rodents.

Small molecule disruptors of the GK-GKRP interaction

255th National Meeting (2018)

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