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- Title
1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.
- Authors
Asquith, Christopher R. M.; Godoi, Paulo H.; Couñago, 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.; Kalogirou, Andreas S.; Besson, Thierry
- Abstract
We demonstrate for the first time that 4<italic>H</italic>-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)-4<italic>H</italic>-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.
- Subjects
PROTEIN kinases; CHROMATOGRAPHIC analysis; MOLECULES; CRYSTAL structure; POLYTYPIC transformations
- Publication
Molecules, 2018, Vol 23, Issue 5, p1221
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules23051221