4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution

J Med Chem. 2006 Aug 10;49(16):4896-911. doi: 10.1021/jm0512591.


High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

MeSH terms

  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Carbazoles / chemical synthesis*
  • Carbazoles / chemistry
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry*
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry*
  • Protein Binding
  • Protein Kinases / chemistry
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / chemistry*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Structure-Activity Relationship


  • Benzene Derivatives
  • Carbazoles
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Pyrroles
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CHEK1 protein, human
  • Checkpoint Kinase 1