Identification and characterization of bi-thiazole-2,2′-diamines as kinase inhibitory scaffolds |
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Authors: | Kevin RW Ngoei Dominic CH Ng Paul R Gooley David P Fairlie Martin J Stoermer Marie A Bogoyevitch |
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Institution: | 1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia;2. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia |
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Abstract: | Based on bioinformatics interrogation of the genome, > 500 mammalian protein kinases can be clustered within seven different groups. Of these kinases, the mitogen-activated protein kinase (MAPK) family forms part of the CMGC group of serine/threonine kinases that includes extracellular signal regulated kinases (ERKs), cJun N-terminal kinases (JNKs), and p38 MAPKs. With the JNKs considered attractive targets in the treatment of pathologies including diabetes and stroke, efforts have been directed to the discovery of new JNK inhibitory molecules that can be further developed as new therapeutics. Capitalizing on our biochemical understanding of JNK, we performed in silico screens of commercially available chemical databases to identify JNK1-interacting compounds and tested their in vitro JNK inhibitory activity. With in vitro and cell culture studies, we showed that the compound, 4′-methyl-N2-3-pyridinyl-4,5′-bi-1,3-thiazole-2,2′-diamine (JNK Docking (JD) compound 123, but not the related compound (4′-methyl-N ~ 2 ~ -(6-methyl-2-pyridinyl)-4,5′-bi-1,3-thiazole-2,2′-diamine (JD124), inhibited JNK1 activity towards a range of substrates. Molecular docking, saturation transfer difference NMR experiments and enzyme kinetic analyses revealed both ATP- and substrate-competitive inhibition of JNK by JD123. In characterizing JD123 further, we noted its ATP-competitive inhibition of the related p38-γ MAPK, but not ERK1, ERK2, or p38-α, p38-β or p38-δ. Further screening of a broad panel of kinases using 10 μM JD123, identified inhibition of kinases including protein kinase Bβ (PKBβ/Aktβ). Appropriately modified thiazole diamines, as typified by JD123, thus provide a new chemical scaffold for development of inhibitors for the JNK and p38-γ MAPKs as well as other kinases that are also potential therapeutic targets such as PKBβ/Aktβ. |
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Keywords: | MAPK mitogen-activated protein kinase JD JNK Docking ERK extracellular signal signal-regulated kinase JNK c-Jun N-terminal kinase MKK MAPK kinase GST glutathione S-transferase GSH glutathione JIP JNK-interacting protein DCX doublecortin X EGFR epidermal growth factor receptor PKB/Akt protein kinase B STD NMR saturation transfer difference nuclear magnetic resonance AMP-PNP adenosine 5&prime -(β γ-imido)triphosphate DMSO dimethyl sulphoxide MEF murine embryonic fibroblast PVDF polyvinylidene fluoride |
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