Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model

J Med Chem. 2020 Jul 9;63(13):6784-6801. doi: 10.1021/acs.jmedchem.9b01803. Epub 2020 Jun 22.


Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / chemistry
  • Diet / adverse effects*
  • Disease Models, Animal
  • Drug Discovery*
  • Insulin Resistance*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Obesity / chemically induced
  • Obesity / drug therapy*
  • Obesity / metabolism*
  • Protein Conformation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use


  • Protein Kinase Inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • Camk1d protein, mouse