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Open AccessArticle

1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors

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Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA
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Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo 13083-886, Brazil
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Center for Molecular and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Cidade Universitária Zeferino Vaz, Avenida Cândido Rondon 400, P. O. Box 6010, 13083-875 Campinas, São Paulo 13083-886, Brazil
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School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland
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St Vincent’s Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia
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Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia
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The Florey Institute of Neuroscience and Mental Health, Parkville 3052, Australia
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Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus
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Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P. O. Box 22006, 1516 Nicosia, Cyprus
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Authors to whom correspondence should be addressed.
Academic Editor: Thierry Besson
Molecules 2018, 23(5), 1221; https://doi.org/10.3390/molecules23051221
Received: 29 April 2018 / Revised: 15 May 2018 / Accepted: 15 May 2018 / Published: 19 May 2018
(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)
We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors. View Full-Text
Keywords: thiadiazinone; hinge binder; kinase inhibitor design; kinase water network; CaMKK2 thiadiazinone; hinge binder; kinase inhibitor design; kinase water network; CaMKK2
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Asquith, C.R.M.; Godoi, P.H.; Couñago, R.M.; Laitinen, T.; Scott, J.W.; Langendorf, C.G.; Oakhill, J.S.; Drewry, D.H.; Zuercher, W.J.; Koutentis, P.A.; Willson, T.M.; Kalogirou, A.S. 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors. Molecules 2018, 23, 1221.

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