Pyridyl aminothiazoles as potent Chk1 inhibitors: optimization of cellular activity

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2613-9. doi: 10.1016/j.bmcl.2012.01.120. Epub 2012 Feb 7.

Abstract

Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinase-Activating Kinase
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / chemistry
  • Drug Design
  • Halogenation
  • Humans
  • Kinetics
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Thiazoles
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinases
  • Cyclin-Dependent Kinase-Activating Kinase
  • CDK7 protein, human