1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

Journal article


Asquith, Christopher R.M., Godoi, Paulo H., Counago, Rafael M., Laitinen, Tuomo, Scott, John W., Langendorf, Christopher G., Oakhill, Jonathan S., Drewry, David H., Zuercher, William J., Koutentis, Panayiotis A., Willson, Timothy M. and Kalogirou, Andreas S.. (2018) 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors. Molecules. 23(5), pp. 1 - 23. https://doi.org/10.3390/molecules23051221
AuthorsAsquith, Christopher R.M., Godoi, Paulo H., Counago, Rafael M., Laitinen, Tuomo, Scott, John W., Langendorf, Christopher G., Oakhill, Jonathan S., Drewry, David H., Zuercher, William J., Koutentis, Panayiotis A., Willson, Timothy M. and Kalogirou, Andreas S.
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.

Year2018
JournalMolecules
Journal citation23 (5), pp. 1 - 23
PublisherMDPI AG
ISSN1420-3049
Digital Object Identifier (DOI)https://doi.org/10.3390/molecules23051221
Scopus EID2-s2.0-85047477636
Open accessOpen access
Page range1 - 23
Research GroupMary MacKillop Institute for Health Research
Publisher's version
Place of publicationSwitzerland
EditorsD.J. McPhee
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