Journal Article

PUBDB-2020-03178

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model

Fromont, C. ; Atzori, A. ; Kaur, D. ; Hashmi, L. ; Greco, G. ; Cabanillas, A. ; Nguyen, H. V. ; Jones, D. H. ; Garzón, M. ; Varela, A. ; Stevenson, B. ; Iacobini, G. P. ; Lenoir, M. ; Rajesh, S. ; Box, C. ; Kumar, J. ; Grant, P. ; Novitskaya, V. ; Morgan, J. ; Sorrell, F. J. ; Redondo, C. ; Kramer, A. ; Harris, C. J. ; Leighton, B. ; Vickers, S. P. ; Cheetham, S. C. ; Kenyon, C. ; Grabowska, A. M. ; Overduin, M. ; Berditchevski, F. ; Weston, C. J. ; Knapp, S. ; Fischer, P. M. ; Butterworth, S. (Corresponding author)

2020
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.9b01803  doi:10.3204/PUBDB-2020-03178

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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2020

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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