1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors
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CitationAsquith, CRM. Godoi, PH. Counago, RM. Laitinen, T. Scott, JW. Langendorf, CG. Oakhill, JS. Drewry, DH. Zuercher, WJ. Koutentis, PA. Willson, TM. Kalogirou, AS. (2018). 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors. MOLECULES, 23 (5) , 1221. 10.3390/molecules23051221.
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.