1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors
Date
2018Author
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.
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Willson, Timothy M.
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Source
MoleculesVolume
23Issue
5Google Scholar check
Metadata
Show full item recordAbstract
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.