Evaluation of substituted 6-arylquinazolin-4-amines as potent and selective inhibitors of cdc2-like kinases (Clk).

Medicinal Chemistry


A series of substituted 6-arylquinazolin-4-amines were prepared and analyzed as inhibitors of Clk4. Synthesis, structure-activity relationships and the selectivity of a potent analogue against a panel of 402 kinases are presented. Inhibition of Clk4 by these agents at varied concentrations of assay substrates (ATP and receptor peptide) highly suggests that this chemotype is an ATP competitive inhibitor. Molecular docking provides further evidence that inhibition is the result of binding at the kinase hinge region. Selected compounds represent novel tools capable of potent and selective inhibition of Clk1, Clk4, and Dyrk1A.


Mott, Bryan T; Tanega, Cordelle; Shen, Min; Maloney, David J; Shinn, Paul; Leister, William; Marugan, Juan; Inglese, James; Austin, Christopher; Misteli, Tom; Auld, Douglas S; Thomas, Craig;


  • Amines/ chemical synthesis
  • Amines/ chemistry
  • Amines/ pharmacology
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors/ chemical synthesis
  • Protein Kinase Inhibitors/ chemistry
  • Protein Kinase Inhibitors/ pharmacology
  • Protein-Serine-Threonine Kinases/ antagonists & inhibitors
  • Protein-Tyrosine Kinases/ antagonists & inhibitors
  • Quinazolines/ chemical synthesis
  • Quinazolines/ chemistry
  • Quinazolines/ pharmacology
  • Structure-Activity Relationship

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