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Molecules. 2018 May 19;23(5). pii: E1221. doi: 10.3390/molecules23051221.

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

Author information

1
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. chris.asquith@unc.edu.
2
Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA. chris.asquith@unc.edu.
3
Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo 13083-886, Brazil. phgodoi@yahoo.com.
4
Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo 13083-886, Brazil. rafaelcounago@gmail.com.
5
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. rafaelcounago@gmail.com.
6
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland. tuomo.laitinen@uef.fi.
7
St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia. jscott@svi.edu.au.
8
Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia. jscott@svi.edu.au.
9
The Florey Institute of Neuroscience and Mental Health, Parkville 3052, Australia. jscott@svi.edu.au.
10
St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia. clangendorf@svi.edu.au.
11
St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia. joakhill@svi.edu.au.
12
Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia. joakhill@svi.edu.au.
13
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. david.drewry@unc.edu.
14
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. william.zuercher@unc.edu.
15
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. william.zuercher@unc.edu.
16
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus. koutenti@ucy.ac.cy.
17
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. tim.willson@unc.edu.
18
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus. kalogirou.andreas@ucy.ac.cy.
19
Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P. O. Box 22006, 1516 Nicosia, Cyprus. kalogirou.andreas@ucy.ac.cy.

Abstract

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.

KEYWORDS:

CaMKK2; hinge binder; kinase inhibitor design; kinase water network; thiadiazinone

PMID:
29783765
PMCID:
PMC6019134
DOI:
10.3390/molecules23051221
[Indexed for MEDLINE]
Free PMC Article

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