Title: 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors
Authors: Asquith, CRM
Godoi, PH
Counago, RM
Laitinen, T
Scott, JW
Langendorf, CG
Oakhill, JS
Drewry, DH
Zuercher, WJ
Koutentis, PA
Willson, TM
Kalogirou, AS
Issue Year: 2018
Publisher MDPI
Series Molecules:
Abstract 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.
URI: https://publications.svi.edu.au/publications/4529
Other Identifiers 10.3390/molecules23051221
Publication type Article