Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity 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 P, Lenoir, Marc, Rajesh, Sundaresan, Box, Clare, Kumar, Jitendra, Grant, Paige, Novitskaya, Vera, Morgan, Juliet, Sorrell, Fiona J, Redondo, Clara, Kramer, Andreas, Harris, C John, Leighton, Brendan, Vickers, Steven P, Cheetham, Sharon C, 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 Obesity Mouse Model. Journal of medicinal chemistry, 63 (13). pp. 6784-6801. ISSN 1520-4804. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs.

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Official URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01...

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 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 validation of CaMK1D as a target for diabetes therapeutics.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs.
Subjects: QV Pharmacology
WK Endocrine system. Endocrinology
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Depositing User: Mrs Noomi Tyholdt-Pidgley
Date Deposited: 29 Jan 2021 10:06
Last Modified: 29 Jan 2021 10:06
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3912

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