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

Molecules. 2018 May 19;23(5):1221. doi: 10.3390/molecules23051221.

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.

Keywords: CaMKK2; hinge binder; kinase inhibitor design; kinase water network; thiadiazinone.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / chemistry
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Thiadiazoles / chemical synthesis*
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*
  • Water / chemistry

Substances

  • Protein Kinase Inhibitors
  • Thiadiazoles
  • Water
  • CAMKK2 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase