Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in...

Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by K_ATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.