Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 1
/ antagonists & inhibitors
Diet
/ adverse effects
Disease Models, Animal
Drug Discovery
Insulin Resistance
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Obesity
/ chemically induced
Protein Conformation
Protein Kinase Inhibitors
/ pharmacology
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
09 07 2020
09 07 2020
Historique:
pubmed:
21
5
2020
medline:
18
11
2020
entrez:
21
5
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 32433887
doi: 10.1021/acs.jmedchem.9b01803
pmc: PMC7445743
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Calcium-Calmodulin-Dependent Protein Kinase Type 1
EC 2.7.11.17
Camk1d protein, mouse
EC 2.7.11.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6784-6801Subventions
Organisme : Medical Research Council
ID : MC_PC_15032
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 103022
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202708
Pays : United Kingdom
Organisme : Wellcome Trust
ID : MC_PC_15032
Pays : United Kingdom
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