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

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Asquith, CRM; Godoi, PH; Couñago, RM; Laitinen, T; Scott, JW; Langendorf, CG; Oakhill, JS; Drewry, DH; Zuercher, WJ; Koutentis, PA; ...Date
2018-05-19Source Title
MoleculesPublisher
MDPI AGAffiliation
Medicine and RadiologyMetadata
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Asquith, C. R. M., Godoi, P. H., Couñago, R. M., Laitinen, T., Scott, J. W., Langendorf, C. G., Oakhill, J. S., Drewry, D. H., Zuercher, W. J., Koutentis, P. A., Willson, T. M. & Kalogirou, A. S. (2018). 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.. Molecules, 23 (5), pp.1221-1221. https://doi.org/10.3390/molecules23051221.Access Status
Open AccessOpen Access at PMC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019134Abstract
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.
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