6t28
Crystal structure of human calmodulin-dependent protein kinase 1D (CAMK1D) bound to compound 19 (CS640)
Structural highlights
FunctionKCC1D_HUMAN Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.[1] [2] [3] [4] Publication Abstract from PubMedPolymorphisms 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. 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 HV, Jones DH, Garzon M, Varela A, Stevenson B, Iacobini GP, Lenoir M, Rajesh S, Box C, Kumar J, Grant P, Novitskaya V, Morgan J, Sorrell FJ, Redondo C, Kramer A, Harris CJ, Leighton B, Vickers SP, Cheetham SC, Kenyon C, Grabowska AM, Overduin M, Berditchevski F, Weston CJ, Knapp S, Fischer PM, Butterworth S J Med Chem. 2020 Jun 22. doi: 10.1021/acs.jmedchem.9b01803. PMID:32433887[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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