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
Authors | 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. |
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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. |
Year | 2018 |
Journal | Molecules |
Journal citation | 23 (5), pp. 1 - 23 |
Publisher | MDPI AG |
ISSN | 1420-3049 |
Digital Object Identifier (DOI) | https://doi.org/10.3390/molecules23051221 |
Scopus EID | 2-s2.0-85047477636 |
Open access | Open access |
Page range | 1 - 23 |
Research Group | Mary MacKillop Institute for Health Research |
Publisher's version | |
Place of publication | Switzerland |
Editors | D.J. McPhee |
https://acuresearchbank.acu.edu.au/item/8558z/1-2-6-thiadiazinones-as-novel-narrow-spectrum-calcium-calmodulin-dependent-protein-kinase-kinase-2-camkk2-inhibitors
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