jm4016735_si_001.pdf (185.63 kB)
Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept
journal contribution
posted on 2014-01-23, 00:00 authored by Kate S. Ashton, Kristin L. Andrews, Marion
C. Bryan, Jie Chen, Kui Chen, Michelle Chen, Samer Chmait, Michael Croghan, Rod Cupples, Christopher Fotsch, Joan Helmering, Steve
R. Jordan, Robert J. M. Kurzeja, Klaus Michelsen, Lewis
D. Pennington, Steve F. Poon, Glenn Sivits, Gwyneth Van, Steve L. Vonderfecht, Robert C. Wahl, Jiandong Zhang, David
J. Lloyd, Clarence Hale, David J. St. JeanSmall
molecule activators of glucokinase have shown robust efficacy
in both preclinical models and humans. However, overactivation of
glucokinase (GK) can cause excessive glucose turnover, leading to
hypoglycemia. To circumvent this adverse side effect, we chose to
modulate GK activity by targeting the endogenous inhibitor of GK,
glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex
results in an increase in the amount of unbound cytosolic GK without
altering the inherent kinetics of the enzyme. Herein we report the
identification of compounds that efficiently disrupt the GK-GKRP interaction
via a previously unknown binding pocket. Using a structure-based approach,
the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both
a robust pharmacodynamic effect as well as a statistically significant
reduction in glucose. Additionally, hypoglycemia was not observed
in either the hyperglycemic or normal rats.