1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors

Christopher R.M. Asquith, Paulo H. Godoi, Rafael M. Cou ago, Tuomo Laitinen, John W. Scott, Christopher G. Langendorf, Jonathan S. Oakhill, David H. Drewry, William J. Zuercher, Panayiotis A. Koutentis, Timothy M. Willson, Andreas S. Kalogirou

Research output: Contribution to journalArticle

  • 1 Citations

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.

LanguageEnglish (US)
Article number1221
JournalMolecules
Volume23
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Kinase
Thiadiazoles
X ray crystallography
Protein Kinase Inhibitors
Molecular structure
Phosphotransferases
Water
Adenosine Triphosphate
Crystal structure
Molecules

Keywords

  • CaMKK2
  • Hinge binder
  • Kinase inhibitor design
  • Kinase water network
  • Thiadiazinone

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Asquith, C. R. M., Godoi, P. H., Cou ago, R. M., Laitinen, T., Scott, J. W., Langendorf, C. G., ... Kalogirou, A. S. (2018). 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors. Molecules, 23(5), [1221]. https://doi.org/10.3390/molecules23051221

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors. / Asquith, Christopher R.M.; Godoi, Paulo H.; Cou ago, 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.

In: Molecules, Vol. 23, No. 5, 1221, 01.01.2018.

Research output: Contribution to journalArticle

Asquith, CRM, Godoi, PH, Cou ago, 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, vol. 23, no. 5, 1221. https://doi.org/10.3390/molecules23051221
Asquith, Christopher R.M. ; Godoi, Paulo H. ; Cou ago, 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. / 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors. In: Molecules. 2018 ; Vol. 23, No. 5.
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