Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

• Published in: Journal of medicinal chemistry Vol. 57; no. 2; pp. 309 - 324
• Main Authors: Ashton, Kate S., Andrews, Kristin L., Bryan, Marion C., Chen, Jie, Chen, Kui, Chen, Michelle, Chmait, Samer, Croghan, Michael, Cupples, Rod, Fotsch, Christopher, Helmering, Joan, Jordan, Steve R., Kurzeja, Robert J. M., Michelsen, Klaus, Pennington, Lewis D., Poon, Steve F., Sivits, Glenn, Van, Gwyneth, Vonderfecht, Steve L., Wahl, Robert C., Zhang, Jiandong, Lloyd, David J., Hale, Clarence, St. Jean, David J.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 23-01-2014
• Subjects: Animals; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Crystallography, X-Ray; Glucokinase - chemistry; Glucokinase - metabolism; Hepatocytes - drug effects; Hepatocytes - metabolism; High-Throughput Screening Assays; Humans; Hypoglycemia - chemically induced; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Piperazines - adverse effects; Piperazines - chemistry; Piperazines - pharmacology; Protein Conformation; Protein Transport; Rats; Rats, Zucker; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - adverse effects; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4016735

Small 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.