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.
Koutentis, Panayiotis A.
Willson, Timothy M.
Kalogirou, Andreas S.
Source
MoleculesVolume
23Issue
5Google Scholar check
Metadata
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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.