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1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors

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

Molecules (Basel, Switzerland), 2018-05, Vol.23 (5), p.1221 [Periódico revisado por pares]

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Título:
1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors
Autor: 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
Assuntos: Bound water ; Ca2+/calmodulin-dependent protein kinase ; Calcium ; Calcium-binding protein ; Calmodulin ; Crystal structure ; Inhibitors ; Kinases ; Molecular chains ; Proteins ; Water chemistry
É parte de: Molecules (Basel, Switzerland), 2018-05, Vol.23 (5), p.1221
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: We demonstrate for the first time that 4 -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)-4 -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.
Editor: Switzerland: MDPI AG
Idioma: Inglês

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