Synthesis and SAR of inhibitors of protein kinase CK2: novel tricyclic quinoline analogs

Bioorg Med Chem Lett. 2012 Jan 1;22(1):45-8. doi: 10.1016/j.bmcl.2011.11.087. Epub 2011 Nov 30.

Abstract

Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Casein Kinase II / antagonists & inhibitors*
  • Casein Kinase II / chemistry
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical / methods
  • Crystallography, X-Ray / methods
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Models, Molecular
  • Protein Conformation
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Quinolines
  • Casein Kinase II