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

Abstract

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.

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases

“…Overall, the risk allele of rs10830963 triggers a cascade of molecular changes facilitating diabetes. The rs11257655 risk allele shows allele-specific binding to FOXA1/FOXA2, thereby upregulating the transcription of CAMK1D, which increases gluconeogenesis and, therefore, the risk of diabetes (Figure 2) [104,105]. The risk allele of rs11257655 is associated with decreased methylation in the promoter region of CAMK1D, supporting the role of DNA methylation in the relationship between the risk allele, FOXA1/FOXA2 binding, and CAMK1D expression [84].…”

Pyronaridine Protects Against SARS-CoV-2 in Mouse

“…Furthermore, we have shown that pyronaridine may target Pl pro as well as CAMK1. There are few inhibitors of CAMK1 that have been identified to date (such as Barettin (62) or pyridine amides (63)) which has a role in inflammation targeting IL-10 (62). Previous in vitro work has shown that inhibiting CAMK1 in cells reduces IL-10, the master anti-inflammatory interleukin (64).…”

Backbone resonance assignments of the catalytic and regulatory domains of Ca2+/calmodulin-dependent protein kinase 1D

“…Following optimization of solution conditions, the autoinhibited human CaMK1D was found to be amenable to NMR analysis, yielding resolved spectra under physiological buffer conditions. This information has been used to aid in the design of small molecule inhibitors of CaMK1D and development of lead candidates for therapeutic intervention (Fromont et al 2020).…”