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Discovery of highly selective inhibitors of calmodulin-dependent kinases that restore insulin sensitivity in the diet-induced obese in vivo mouse model

Fromont, Christophe, Atzori, Alessio, Kaur, Divneet, Hashmi, Lubna, Greco, Graziella, Cabanillas, Alejandro, Nguyen, Huy Van, Jones, D. Heulyn, Garzón, Miguel, Varela, Ana, Stevenson, Brett, Iacobini, Greg, Lenoir, Marc, Rajesh, Sundaresan, Box, Clare, Kumar, Jitendra, Grant, Paige, Novitskaia, Vera, Morgan, Juliet, Sorrell, Fiona, Redondo, Clara, Kramer, Andreas, Harris, C. John, Leighton, Brendan, Vickers, Steven, Cheetham, Sharon, Kenyon, Colin, Grabowska, Anna M., Overduin, Michael, Berditchevski, Fedor, Weston, Chris J, Knapp, Stefan, Fischer, Peter M. and Butterworth, Sam 2020. Discovery of highly selective inhibitors of calmodulin-dependent kinases that restore insulin sensitivity in the diet-induced obese in vivo mouse model. Journal of Medicinal Chemistry 63 (13) , pp. 6784-6801. 10.1021/acs.jmedchem.9b01803

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Chemical Society
ISSN: 0022-2623
Date of Acceptance: 20 May 2020
Last Modified: 04 Aug 2020 13:17
URI: http://orca.cf.ac.uk/id/eprint/131919

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