1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors
Ημερομηνία
2018Συγγραφέας
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
Εμφάνιση πλήρους εγγραφήςΕπιτομή
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.