Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B

J Med Chem. 2012 Nov 8;55(21):9312-30. doi: 10.1021/jm301034u. Epub 2012 Oct 8.

Abstract

DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Alkaloids / pharmacology
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / cytology
  • Brain / drug effects
  • Cell Death / drug effects
  • Cell Line
  • Chromatography, Affinity
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / chemistry
  • Dioxoles / chemical synthesis*
  • Dioxoles / chemistry
  • Dioxoles / pharmacology
  • Glutamic Acid / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology
  • Porifera / chemistry*
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Pyramidal Cells / cytology
  • Pyramidal Cells / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • ((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one)
  • Alkaloids
  • Amyloid beta-Protein Precursor
  • Dioxoles
  • Imidazoles
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • Glutamic Acid
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 2

Associated data

  • PDB/4AZE
  • PDB/4AZF
  • PDB/4GW8